Wiley: Immunology: Table of Contents

Issue Information

Sun, 07 Jun 2026 17:51:15 -0700

Immunology, Volume 178, Issue 3, July 2026.

Monocyte‐Derived Alveolar Macrophages in ALI/ARDS: The Core Drivers of Inflammation

Zhouli Tan, Yiwei Ding, Wei Chen, Chunyang Zhang, Zhihai Han, Xuxin Chen — Sun, 07 Jun 2026 17:51:15 -0700

This review characterises the dynamic shifts between tissue-resident alveolar macrophages (TR-AMs) and monocyte-derived alveolar macrophages (Mo-AMs) throughout the lifespan and during the progression of ALI/ARDS. We highlight how Mo-AMs infiltrate the lungs during acute injury, their persistence as key inflammatory drivers and their gradual replacement of TR-AMs during the aging process. These insights position Mo-AMs as a central therapeutic target for modulating lung inflammation and subsequent fibrosis.

ABSTRACT

Acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) is a deadly disorder with poor therapeutic opportunities, driven by dysregulated immunity. Here we position monocyte-derived alveolar macrophages (Mo-AMs) as central mediators of ALI/ARDS pathogenesis, contrasting with homeostatic tissue-resident alveolar macrophages (TR-AMs). This review first traces the origin pathway of Mo-AMs, which differentiate from haematopoietic stem cells (HSCs) in the bone marrow and are recruited to the inflamed lung via a CCR2/CCL2-dependent pathway, ultimately differentiating into pathogenic effector cells within the alveolar microenvironment. Subsequently, we elucidate their primary pathogenic mechanisms: Mo-AMs mediate critical pathological injury by generating cytokine storms, depleting TR-AMs, disrupting the alveolar-capillary barrier and promoting fibrotic remodelling. Given their well-defined pathogenic role, Mo-AMs have emerged as a promising therapeutic target. Therefore, we conclude by reviewing recent advances in strategies targeting Mo-AMs, primarily encompassing the inhibition of their recruitment, induction of their apoptosis and reprogramming of their proinflammatory functions. These approaches collectively provide valuable insights for developing novel therapies for ALI/ARDS.

Thymus and Leishmania at the Crossroads: Autoimmunity and Cancer

Sun, 07 Jun 2026 17:51:15 -0700

Conceptual ‘Crossroads Model’ linking Leishmania, thymic infection and immune dysregulation: an integrative model is proposed in which Leishmania infection disrupts thymic architecture and stromal–thymocyte interactions. These alterations converge to promote defective tolerance, increased autoimmune risk and a microenvironment permissive to malignant transformation, driven by insufficient immunovigilance.

ABSTRACT

Leishmania infections profoundly reshape host immunity, yet their impact on central T-cell development remains underappreciated. The thymus, a key site for establishing a functional and self-tolerant T-cell repertoire, is highly sensitive to systemic inflammatory cues. Growing evidence indicates that parasitic diseases, including leishmaniasis, can perturb thymic structure and function through direct parasite presence or sustained inflammatory stress. Such disturbances may alter thymocyte maturation, leading to reduced T-cell output and the release of cells with aberrant specificity. Beyond compromising protective immunity, these changes may create conditions favourable to immune dysregulation, including the emergence of autoimmune manifestations and a microenvironment permissive to malignant transformation. This narrative review synthesises current findings on how Leishmania interacts with immunological tissues and highlights the thymus as a potential and overlooked target whose dysfunction may bridge infection, autoimmunity and cancer.

Strategies of AI‐Driven CAR‐T Cell Therapy Towards Solid Tumours

Ahmed M. E. Abdalla, Yu Miao, Yasir A. Taha, Ning Meng, Chenxi Ouyang — Sun, 07 Jun 2026 17:51:15 -0700

The emergence of AI-driven strategies significantly enhances the efficacy of CAR-T cell therapy towards solid tumours. They can improve CAR design and manufacturing process, providing a novel modular, end-to-end AI platform for CAR construction and development. AI approaches, particularly DL, can provide basic and advanced frameworks to quickly identify potential targets, including multi-antigens, neoantigens, and tumour stromal antigens. In addition, AI-driven innovations can detect the cellular heterogeneity of the TME, mitigate CD8⁺ T exhaustion, facilitate CAR-T cell trafficking, and predict the dynamic behaviour of CAR-T cells, breaking down the complexity of solid tumours.

ABSTRACT

Chimeric antigen receptor (CAR)-T cell immunotherapy shows significant success in hematologic malignancies. However, it faces critical challenges in solid tumours, such as suppressive tumour microenvironment (TME) and antigenic heterogeneity, highlighting the urgent need for effective and safe CAR products. The integration of artificial intelligence (AI) into CAR-T cell immunotherapy offers exceptional opportunities to improve its therapeutic efficacy. More specifically, this paper highlights the transformative role of AI in addressing key challenges that impede the success of CAR-T cell therapy in solid tumours, including assisting in CAR design and manufacturing process, identifying novel CAR-targeted genes, and detecting cell heterogeneity in solid tumours. We remain optimistic about AI-driven strategies for enhancing CAR T-cell persistence, trafficking, and visualisation in the TME. In addition, we highlight the current challenges and prospects for advancing AI-driven CAR-T cell therapies.

Dual TLR7/8 Activation by Dihydroxyimidazoquinoline Adjuvant Orchestrates NF‐κβ‐iNOS‐Driven Th1 Immunity and Durable Protection Against Leishmania donovani

Sun, 07 Jun 2026 17:51:15 -0700

A dihydroxyimidazoquinoline-based TLR7/8 agonist (dh-BBIQ) used as an adjuvant with heat-killed Leishmania donovani antigen induced durable Th1-biased immunity in a murine visceral leishmaniasis model. Immunisation enhanced NF-κB/iNOS activation, ROS and NO production and CD4⁺/CD8⁺ T-cell responses, resulting in sustained reduction of splenic parasite burden up to 16 weeks post-challenge.

ABSTRACT

Targeting Toll like receptors (TLRs) signalling represents a powerful approach to re-calibrate host immunity against intracellular pathogens. Among these, dual TLR7/8 agonists uniquely bridge innate and adaptive immune response through NF-κβ-associated cytokine programming and activation of innate effector pathways. Here we, identify and characterise a dihydroxyimidazoquinoline-based TLR7/8 agonist as a potent immunomodulatory adjuvant that enhances the efficacy of heat-killed Leishmania donovani antigen vaccine in BALB/c mice. Comparative immunisation with escalating adjuvant doses (10, 25 and 50 μg) demonstrated a robust, dose-dependent reduction in splenic parasite burden, accompanied by sustained elevation of Th1 cytokine (IFN-γ and TNF-α) and suppression of Th2-associated cytokine (IL-10 and IL-13) up to 16-week post-challenge. Enhanced iNOS and NF-κβ gene expression, together with elevated ROS and NO production, indicated activation of host effector pathways underlying parasite clearance. Flow cytometric analysis revealed persistent expansion of both CD4⁺ and CD8⁺ T cell subsets in the high-dose groups supporting durable adaptive immunity. The dual TLR7/8 activity of this compound mediated broad and sustained immunoregulatory signalling that surpassed resiquimod in magnitude and persistence. Collectively, this study delineated a mechanistic framework for TLR7/8 driven immunoregulation and establishes dihydroxyimidazoquinoline as a next-generation adjuvant for rational, host-directed vaccine design against intracellular pathogens such as L. donovani .

Mycobacterium avium Subsp. paratuberculosis and Human Endogenous Retrovirus in Italian Patients With Inflammatory Bowel Disease (IBD) and Irritable Bowel Syndrome (IBS)

Sun, 07 Jun 2026 17:51:15 -0700

Inflammatory bowel disease (IBD), comprising ulcerative colitis (UC) and Crohn's disease (CD), is a recognised gastrointestinal disorder. Mycobacterium avium subspecies paratuberculosis (MAP) is implicated in IBD pathogenesis. Persistent exposure and active infections by MAP may contribute to the unsilencing of human endogenous retroviruses (HERV) sequences. This interaction could justify the pathogenesis of IBD by promoting HERV antigen expression and triggering autoantibody production. In addition, specific genetic profiles may exacerbate inflammation, potentially amplifying genetic damage observed in IBD patients, as indicated by MNi frequencies.

ABSTRACT

Inflammatory bowel disease (IBD), comprising ulcerative colitis (UC) and Crohn's disease (CD) and irritable bowel syndrome (IBS) are distinct gastrointestinal disorders. Mycobacterium avium subspecies paratuberculosis (MAP) is implicated in IBD pathogenesis, while the roles of human endogenous retroviruses (HERVs) are under investigation. We aimed (a) to investigate whether the levels of humoral response to MAP-3865c, HERV-K envelope and HERV-W envelope against the epitopes in IBD/IBS patients; (b) to determine the frequency of micronuclei in IBD patients and (c) to evaluate the possible correlation between genomic damage and humoral response. This study investigates antibody titres against MAP 3865c, HERV-K env and HERV-W env in plasma from 102 IBD, 20 IBS patients and 92 healthy controls (HCs). Micronuclei (MNi) frequency in IBD patients is assessed, correlating with humoral responses and patient genotype profiles. IBD patients exhibited elevated antibody responses to MAP 3865c, with those carrying the GA genotype for TNF-α showing higher anti-MAP 3865c IgG levels. A significant positive correlation was observed between MNi frequency and the humoral response against MAP 3865c in IBD patients. Higher antibody responses to HERV-K env were detected in both IBD and IBS patients compared to HCs, with significant positive correlations found between MAP 3865c and HERV-K env peptide responses in IBD patients. HERV-W env antibody levels were higher in IBS patients than in HCs. Our findings highlight the association between UC and CD and immune responses targeting MAP and HERV-Kenv. Specific genetic profiles may exacerbate inflammation, potentially amplifying genetic damage observed in IBD patients, as indicated by MNi frequencies.

A Bioluminescence Reporter Mouse Strain for In Vivo Imaging of IFNγ Cell Localization and Function

Sun, 07 Jun 2026 17:51:15 -0700

CRISPR/Cas9-mediated generation of a C57BL/6J-Ifng-2A-luciferase knock-in mouse enables real-time bioluminescence imaging of IFNγ-expressing cells. The model is applied to Poly(I:C)-induced transient IFNγ expression, intratumoral IFNγ responses during anti-PD-1/CTLA-4 therapy and IFNγ dynamics in imiquimod-induced psoriasis.

ABSTRACT

Interferon gamma (IFNγ) is a pivotal inflammatory mediator and immune regulator, but its in vivo spatiotemporal dynamics and functional roles in inflammation and carcinogenesis remain incompletely understood. Here, we developed a C57BL/6J- Ifng-2A-luciferase knock-in mouse strain using CRISPR/Cas9-mediated homology-directed repair, enabling real-time bioluminescence imaging (BLI) of IFNγ-expressing cells by inserting a luciferase cassette under the endogenous Ifng promoter. The validation confirmed that this model is capable of directly detecting Poly(I:C) -induced transient IFNγ, enhancing intratumoral IFNγ signals upon anti-PD-1/CTLA-4 therapy, and dynamically tracking IFNγ expression during imiquimod-induced psoriasis. This transgenic mouse model provides a powerful tool for non-invasive, longitudinal tracking of IFNγ-expressing cells, offering novel insights into IFNγ-mediated immune regulation in inflammation and cancer. It holds promise for identifying IFNγ-related therapeutic targets and predicting responses to immunotherapies.

Gut Microbiota‐Induced CTLA4 Expression on CD8 + T Cells Impairs Antitumor Immunity and Promotes Colorectal Cancer Progression

Meidie Cheng, Shuangcheng Zhi, Mengmeng Zheng, Sijin Zhang, Jun Hong — Sun, 07 Jun 2026 17:51:15 -0700

Specific molecular mechanisms of the interaction between CTLA4⁺CD8⁺ double-positive T cells in the CRC tumour microenvironment and intestinal flora.

ABSTRACT

This study reveals a novel gut microbiota-CD8⁺ T cell axis driving immunosuppression in colorectal cancer. Analysis of 16S rRNA sequencing identified significant gut dysbiosis in CRC patients, with marked enrichment of Phocaeicola and Bacteroides. Single-cell transcriptomics uncovered substantial T cell depletion and elevated CTLA4⁺PD1⁺ immune cells within the tumour microenvironment. Critically, spatial transcriptomics demonstrated co-localization of CTLA4⁺CD8⁺ T cells with tumour cells, indicating direct immunosuppressive interactions. Functional validation confirmed CTLA4 overexpression impairs CD8⁺ T cell effector capacity, accelerating CRC cell proliferation and invasion. In vivo models demonstrated that faecal microbiota transplantation (FMT) promoted CTL activation, reduced Bacteroides abundance, decreased the formation of CD8⁺CTLA4⁺ T cells and ameliorated CRC symptoms. Additionally, CTLA4 knockdown inhibited tumour growth and metastasis. These findings establish a mechanistic pathway: gut dysbiosis induces chronic inflammation, triggering CTLA4 upregulation on CD8⁺ T cells to promote T cell exhaustion and tumour immune evasion. The study provides immunological evidence for targeting the microbiota-CTLA4 axis in CRC immunotherapy.

SIRT6 Ameliorates Atherosclerosis by Inhibiting M1 Macrophage Polarisation Through Deacetylated‐TLR4

Jian Huang, Huiming Yi, Yanhui Wu, Wei Zhang, Xi Ai — Sun, 07 Jun 2026 17:51:15 -0700

SIRT6 is downregulated in atherosclerosis; it enhances TLR4 stability by promoting TLR4 acetylation, thereby facilitating macrophage M1 polarisation and subsequently accelerating atherosclerosis progression.

ABSTRACT

Atherosclerosis serves as the fundamental pathological process underlying numerous cardiovascular disorders, and the change of macrophage polarisation is the key to regulate the inflammatory response of AS. SIRT6 plays a protective effect in AS, but whether it regulates macrophage polarisation in AS remains uncertain. We aimed to characterise the mechanistic role of SIRT6 in atherosclerosis development mediated by macrophage polarisation. ApoE^−/− mice were fed a Western diet to construct the AS mouse model, and LPS treatment was performed on RAW264.7 cells to induce an inflammation cell model. Quantitative real-time PCR was performed to measure the expression of SIRT6 and M1/M2 macrophage polarisation markers. Plaque size was evaluated by Oil red O staining. M1/M2 macrophage polarisation was evaluated by immunofluorescence staining. The underlying mechanism was determined by Western blot, immunoprecipitation (IP), and co-IP. Results suggested that SIRT6 was downregulated in the AS mouse model and LPS-induced macrophages. SIRT6 overexpression decreased plaque size and blood lipid levels in the AS mouse model and inhibited macrophages polarisation to the M1-like phenotype both in vivo and in vitro. Mechanically, SIRT6 overexpression downregulated the protein level of TLR4 by decreasing acetylation on TLR4. Moreover, TLR4 overexpression restored M1 macrophage polarisation in LPS-induced macrophages inhibited by SIRT6 overexpression. In conclusion, we demonstrated that SIRT6 attenuated AS by suppressing M1 macrophage polarisation through downregulating TLR4 by deacetylation. These results may provide a potential therapeutic target for targeted macrophage polarisation therapy for AS.

STING Drives Psoriatic Inflammation by Promoting Neutrophil Recruitment and Facilitating NETosis

Sun, 07 Jun 2026 17:51:15 -0700

Activation of STING in neutrophils promotes psoriatic inflammation by driving the IRF3/NF-κB-dependent production of pro-inflammatory cytokines, enhancing chemotaxis and tissue infiltration and facilitating the formation of NETs.

ABSTRACT

Psoriasis is a chronic, immune-mediated inflammatory disorder in which neutrophils are central to pathogenesis. While recent studies have implicated the cyclic GMP-AMP synthase–stimulator of interferon genes (cGAS-STING) pathway in psoriasis, its specific role in neutrophil-mediated inflammation remains unclear. To investigate neutrophil function in psoriasis, we integrated single-cell RNA-seq from human lesions with studies in IMQ-treated mouse models (wild-type, STING−/−, PADi4−/−) and HL-60 cells. We employed transcriptomic, cytometric and functional assays to assess neutrophil recruitment, cytokine secretion and neutrophil extracellular trap (NET) formation. Our study revealed significant upregulation of STING expression in both lesional and peripheral blood neutrophils of psoriasis patients. In the IMQ-induced mouse model, STING knockout markedly alleviated disease severity, reduced neutrophil infiltration and suppressed IL-1β release. Mechanistically, STING promoted neutrophil chemotactic migration via the IRF3/NF-κB axis while directly regulating the formation of NETs in neutrophils and the release of cytotoxic mediators. Besides, distinct mouse strains exhibited significant differences in STING pathway activation, indicating genetic heterogeneity in the immunoregulatory mechanisms underlying psoriasis. Collectively, the above findings indicated that STING signalling in neutrophil-mediated psoriatic inflammation not only regulates cell recruitment but also directly drives the terminal effector function of NETs production. Furthermore, strain-specific differences suggest that the regulation of this pathway in the disease context is complex and context-dependent, potentially influencing individualised therapeutic responses. Targeting the STING pathway could serve as a therapeutic strategy to simultaneously inhibit multiple pathogenic processes mediated by neutrophils.

Blood Immunopathology of Tuberculosis Patients Disrupts Monocyte‐Dependent T‐Cell Activation and Cytokine Expression

Sun, 07 Jun 2026 17:51:15 -0700

TB serum selectively disrupts monocyte-dependent PHA T cell activation and cytokines associated with proliferation while preserving SEB T cell and Pam3/PHA monocyte cytokine responses.

ABSTRACT

Pulmonary tuberculosis in humans is characterised by features of immunopathology, which influence both antimycobacterial therapy and the long-term prognosis. In the blood of tuberculosis patients, immunopathology manifests itself in reduced immune responses to mitogenic substances. Previous studies have demonstrated the influence of tuberculosis serum on T-cell and monocyte function, but the exact mechanisms remain unclear. Here, we performed a case/control study to analyse the influence of tuberculosis serum milieu changes on (i) T-cell stimulation (using Staphylococcal Enterotoxin B), (ii) monocyte stimulation (using the Toll-like receptor agonist Pam3CSK4), (iii) T-cell/monocyte interaction characterised by the response against the lectin phytohemagglutinin, by using a novel peripheral blood mononuclear cell in vitro assay. Cell-specific activation marker and cytokine expression were determined by multicolor flow cytometry. Staphylococcal Enterotoxin B mainly induced cytokine expression by T cells, while Pam3CSK4 stimulated monocytes to secrete distinct cytokine signatures. Phytohemagglutinin induced activation and cytokine expression in both T cells and monocytes. Notably, tuberculosis patient serum samples affected exclusively phytohemagglutinin stimulated T-cell responses and particularly activation marker as well as CD40L/IL-2 positive CD4⁺ T-cell subsets were decreased as compared to serum from healthy contacts. Neither Staphylococcal Enterotoxin B-mediated T-cell stimulation nor phytohemagglutinin or Pam3CSK4 induced monocyte cytokines (i.e., Interleukin-6, Interleukin-8, Tumour Necrosis Factor-α) were affected by the tuberculosis patients' serum samples. These results highlight the immunosuppressive influence of the tuberculosis serum milieu, which specifically reduced T-cell responses to phytohemagglutinin, probably through impaired function of the accessory monocytes required for stimulation.

Characterization of T‐Cell Ubiquitination in Melanoma and Development of a Risk Signature Using Single‐Cell and Bulk RNA‐Seq

Jianping Lu, Cheng Lin, Wei Gao, Jie Liu, Yucai Lin, Yu Chen, Jiani Xiong — Sun, 07 Jun 2026 17:51:15 -0700

To clarify the prognostic role of ubiquitination-related genes (URGs) in cutaneous melanoma (CM) immunity, this study integrated single-cell and bulk RNA-seq data. A signature of 6 URGs (UBE2L6, SPSB1, PSMB9, PSMB10, RNF213, ATXN3) stratified CM patients into high- and low-risk groups, showing significant prognostic value and association with immunosuppressive microenvironments—low-risk patients had enriched immune-related pathways. Notably, PSMB9 expression positively correlated with CD8⁺ T cell infiltration. Single-cell analysis confirmed T cells as the main site of this signature's activity, indicating ubiquitination regulates T cell function and CM progression, offering new insights for immunotherapy.

ABSTRACT

Cutaneous melanoma (CM) is an aggressive cancer where early intervention is crucial, but the prognostic role and mechanisms of ubiquitination-related genes (URGs) in immune regulation remain unclear. This study aimed to develop a URG-based prognostic signature and explore its relationship with immune modulation in CM. We integrated single-cell RNA sequencing (scRNA-seq) and bulk RNA-seq data, identifying prognostic URGs through univariate and multivariate Cox regression. A six-gene signature (UBE2L6, SPSB1, PSMB9, PSMB10, RNF213 and ATXN3) was established and validated. The signature effectively stratified patients into high- and low-risk groups, with significant survival differences. Pathway analysis revealed immune-related processes, such as ‘cytokine-cytokine receptor interaction’ and ‘antigen processing and presentation’, enriched in the low-risk group. Immune cell infiltration analysis demonstrated significant differences in the abundance of 12 immune cell types between risk groups. Notably, PSMB9 expression was positively correlated with CD8⁺ T cell abundance (r = 0.64, p < 0.05). scRNA-seq analysis highlighted T cells as a key cell type, with all six prognostic genes showing dynamic expression changes during T cell differentiation. Our findings suggest that URGs influence CM prognosis by modulating the immune microenvironment, offering new insights for immunotherapeutic strategies.

Immunological Reprogramming by Radiation Therapy: Implications for Precision Cancer Treatment

Arun Kumar Singh, Vikash Chand Sharma, Manish Kumar, Manoj Kumar Mishra — Tue, 02 Jun 2026 09:01:09 -0700

Immunological radiation potential in cancer treatment.

ABSTRACT

Radiation therapy (RT) is a main part of cancer treatment and is known mostly for its ability to directly kill cancer cells. However, recent studies have shown that RT can have potent immunomodulatory properties, which include both the ability to re-program the tumour microenvironment (TME) and the activation of systemic anti-tumour immune responses. It reviews the immune mechanisms involved in the killing of tumours after irradiation, such as immunogenic cell death (ICD), activation of the cGAS–STING (cyclic GMP–AMP synthase–stimulator of interferon genes) pathway, dendritic cell (DC) maturation, priming of cytotoxic T lymphocytes (CTLs), and the abscopal effect, which refers to the regression of non-irradiated tumours following local irradiation. We also discuss how RT induces immunosuppressive counterforces such as regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs), and programmed death-ligand 1 (PD-L1) upregulation. The synergy between RT and immune checkpoint inhibitors (ICIs) such as anti-programmed cell death protein 1 (anti-PD-1), anti-programmed death-ligand 1 (anti-PD-L1), and anti-cytotoxic T-lymphocyte-associated protein 4 (anti-CTLA-4) agents is critically assessed. We also discuss possible clinically relevant enhancement of side effects of immunotherapies by RT. The induction of neo-antigens and immune activation by chemotherapy (ChX) versus RT is compared/contrasted. Particular focus is paid to dose fractionation approaches, such as stereotactic body radiation therapy (SBRT) and stereotactic radiosurgery (SRS), and their differential immunogenic effects. The different tumour types that are most susceptible to radiotherapy-induced immunologic responses are covered in great detail, particularly malignant melanoma. The field is contextualised with relevant clinical trials, emerging patents, and translational case studies. In this review, we seek to give an integrative framework for how radiation-induced immune reprogramming can be harnessed in the design of next-generation precision oncology strategies.

Characterisation of HIV‐1 Gag Cytotoxic T‐Lymphocyte Epitopes in the Southern African Region—A Systematic Review

Sun, 31 May 2026 19:35:08 -0700

Distribution of studies on HIV-1 Gag cytotoxic T-lymphocyte epitopes in the southern African region showing that the majority of studies (58.44%) were conducted in South Africa, followed by Botswana (15.58%), Zambia (10.39%), Malawi (7.79%), Zimbabwe (6.49%), and Angola (1.30%). There were no studies found in Eswatini, Lesotho, Madagascar, Mozambique, and Namibia.

ABSTRACT

During early HIV-1 infection, robust Cytotoxic T-lymphocyte (CTL) responses are mostly targeted at immunodominant Gag p24 epitopes to reduce HIV-1 viraemia to a set-point. The aim of this study was to review the current body of knowledge on HIV-1 Gag CTL epitopes in the southern African region where subtype C is prevalent. Peer-reviewed records were obtained from three databases: PubMed Central, Web of Science Core Collection, and Scopus, using the following search terms: HIV subtype C Gag epitopes, and HIV clade C Gag epitopes. The search results were restricted to countries within the southern African region, and only data published in English and between the years 2000–2025 were considered for this review. The search from the three databases produced a total of 2103 peer-reviewed records, and 49 records were included in the review. The majority of studies (58.44%) were conducted in South Africa, followed by Botswana (15.58%), Zambia (10.39%), Malawi (7.79%), Zimbabwe (6.49%) and Angola (1.30%). There were no studies identified from other southern African countries. A total of 60 Gag CTL epitopes were identified, of which 17 (28.33%) were located within the matrix protein (p17), 33 (55.00%) within the capsid protein (p24), and 4 (6.67%) within the Gag polyprotein (p2p7p1p6). The commonly detected immunodominant epitopes were mostly located within the Gag p24 protein; and included TPQDLNTML (TL9, Gag p24 48–56) and TSTLQEQIGW (TW10, Gag p24 108–117) present at 16.00% and 13.3%, respectively. The proportion of HLA-A, B and C allotypes in this systematic review were 18%, 78%, and 4%, respectively. The more common HLA-B allotypes that restrict immunodominant Gag epitopes and facilitate better control of HIV-1 were HLA-B*57, -B*58:01, -B*42:01 and -B*81:01. This systematic review has provided important insights into the description of immunodominant Gag epitopes and HLA-I alleles that contribute to the control of HIV-1 viraemia in the southern African region. It has also exposed that some CTL epitopes identified in the southern African studies are not reported on the Los Alamos HIV database (LANL HIV database). This highlights a need to have this database updated with this information as it is used as a reference for epitopes. This review could provide insights into the design of an epitope-based HIV-1 vaccine that would also be effective in the southern African region.

Neutrophil Secretory Proteins Inhibit Calcium Oxalate Crystallisation and Crystal Growth, but Promote Crystal Aggregation

Chanettee Lertprapai, Paleerath Peerapen, Visith Thongboonkerd — Thu, 28 May 2026 22:00:10 -0700

Calcium oxalate monohydrate (COM) crystals cause changes in the secretion of 29 proteins from neutrophil-like cells, including those involved in neutrophil immune activation and intracellular metabolic adaptation. The neutrophil secreted proteins (secretome) also inhibit calcium oxalate crystallisation and crystal growth, but promote crystal aggregation, suggesting their roles in kidney stone pathogenesis.

ABSTRACT

Neutrophil secretory proteins are frequently found in calcium oxalate (CaOx) kidney stone matrix, suggesting their involvement in stone pathogenesis, but with unclear mechanisms. We therefore investigated the effects of secretome (a set of secretory proteins) from CaOx monohydrate (COM)-exposed versus control dHL-60 (neutrophil-like) cells on crystal nucleation (crystallisation), growth, aggregation and invasion. Quantitative proteomics was also performed to identify significantly altered secretory proteins, followed by analyses of their physicochemical properties and biological relevance. The data demonstrated that both COM-treated and control secretomes inhibited crystallisation and crystal growth, but the inhibitory effects from the COM-treated secretome were slightly weaker. By contrast, both of them promoted crystal aggregation, with the more potent effect from the COM-treated secretome. However, neither of them had a modulatory effect on crystal invasion. Quantitative proteomics revealed 20 decreased and 9 increased proteins in the COM-treated secretome compared with the control. Analyses of physicochemical properties showed that the increased secretory proteins tended to have a lower instability index and a smaller number of oxalate-binding motifs/protein. Main molecular functions of the increased group were catalytic, hydrolase and transporter activities, whereas those of the decreased group included RNA binding, molecular adaptor activity and catalytic activity. These data indicate that the neutrophil secretome inhibits crystallisation and crystal growth but promotes crystal aggregation. The COM-treated secretome exerts weaker inhibitory effects on crystallisation and growth but has a stronger promoting effect on crystal aggregation. These findings enhance our understanding of the roles of neutrophils in kidney stone pathogenesis.

Reprogramming Autophagy to Strengthen Antitumour Immunity: Advances in Immunotherapeutic Strategies

Fri, 22 May 2026 08:05:52 -0700

Tumour-supportive autophagy promotes immune escape by reducing antigen presentation and reinforcing an immunosuppressive tumour microenvironment. Therapeutic autophagy modulation may reprogram these pathways, restore antitumour immunity, and enhance CTL/NK cell activity.

ABSTRACT

Autophagy is a central cellular process that supports homeostasis, yet it also plays a critical part in tumour immune evasion and treatment resistance, creating substantial obstacles for contemporary cancer immunotherapy. Because of this dual nature, targeted modulation of autophagy in either tumour cells or immune cells holds considerable potential to enhance therapeutic outcomes. However, the successful integration of autophagy directed strategies requires a clearer understanding of the molecular pathways through which autophagy shapes immune activity and treatment response. A more refined view of autophagy within the tumour immune microenvironment may open new therapeutic opportunities. Selectively targeting specific autophagy pathways could help overcome immune resistance and strengthen the impact of immunotherapy. Progress in this field will likely depend on the development of delivery systems that allow precise control of tumour autophagy in a compartment specific manner, as well as combination approaches that complement emerging treatments. Incorporating insights from immuno oncology, metabolic regulation, and immune surveillance may accelerate the translation of novel autophagy modulators into clinical testing, although current progress remains shaped largely by preclinical and early translational evidence.

Gastric Cancer‐Derived Exosomal MATN3 Favours Immunosuppressive Tumour Microenvironment by Activating Autophagy in an EGFR/ELK1/ATG12 Signalling Dependent Manner

Wed, 20 May 2026 22:40:19 -0700

GC-delivered exosomal MATN3 interacted with EGFR to activate ELK1 that subsequently triggered ATG12 transcription to induce autophagy, thereby facilitating immunosuppressive M2 macrophage polarisation to drive GC tumourigenesis.

ABSTRACT

Gastric cancer (GC)-derived exosomes (Exos) have been identified to facilitate GC progression by inducing M2 macrophage polarization. This study investigated the biological function of exosomal matrilin-3 (MATN3) in M2 macrophage polarisation during GC development and its underlying mechanism. Exos were isolated from GC cells and then co-cultured with THP-1-derived macrophages. Macrophage polarisation was evaluated by measuring the levels of M1/M2 macrophage markers. Target molecule expression was evaluated by RT-qPCR, Western blotting and immunohistochemical staining. LC3II expression and the co-localisation of MATN3 and epidermal growth factor receptor (EGFR) were determined by immunofluorescent staining. In vivo growth of GC cells was assessed in a xenograft mouse model. Molecular mechanisms were analysed by Co-IP, ChIP, dual-luciferase reporter assay and ubiquitination assay. MATN3 was highly expressed in GC and its high expression was negatively associated with the overall survival and M1 macrophage marker expression of GC patients. The in vitro experiments validated that MATN3 was secreted by GC-Exos, which promoted M2 macrophage polarisation via autophagy activation. In addition, exosomal MATN3 contributed to in vivo growth of GC cells via promoting M2 macrophage infiltration. Mechanistically, MATN3 interacted with EGFR to enhance its protein stability, which activated Ets-like protein-1 (ELK1) and consequently promoted ATG12-mediated autophagy. Activation of the EGFR/ELK1 pathway abolished exosomal MATN3 silencing-mediated inhibitory effect on autophagy and M2 macrophage polarisation. GC-derived exosomal MATN3 exerted an oncogenic role by inducing M2 macrophage polarisation via activation of the EGFR/ELK1/ATG12 axis-mediated autophagy, which provides potential therapeutic targets for GC.

Current Status of Treg Therapy in Transplantation and Autoimmune Disease

Hongwen Li, Huimin Zeng — Wed, 20 May 2026 02:43:23 -0700

In this work, we systematically reviewed the preclinical studies and clinical applications of Treg-based therapies. We briefly discuss the classification of Tregs and their immunoregulatory mechanisms. We provide a comprehensive overview of preclinical studies and clinical applications of adoptive Treg therapy and low-dose IL-2 therapy in GVHD, solid organ transplantation and various autoimmune disorders. In addition, we discuss the application of CAR-Treg (a modified Treg with targeted properties and enhanced inhibitory effects).

ABSTRACT

Regulatory T cells (Tregs) represent a critical subset of T lymphocytes essential for maintaining immune homeostasis. Through diverse molecular mechanisms, Tregs exert potent immunosuppressive effects that preserve self-tolerance and mitigate aberrant immune activation. Dysregulation in Treg frequency or function is closely associated with the development of various immune-mediated disorders. This has prompted extensive preclinical investigations and clinical trials evaluating the therapeutic potential of Tregs in conditions such as graft-versus-host disease, solid organ transplantation, and autoimmune diseases, which have yielded promising outcomes. This review provides a comprehensive overview of current preclinical and clinical applications of Treg-based therapies, including adoptive Treg transfer, low-dose IL-2, and CAR-Treg therapy, and discusses their effectiveness in modulating immune responses across diverse pathological contexts.

IFI16/204 Promotes Dendritic Cell Activation and Anti‐Hepatocellular Carcinoma Efficacy via the STING–TBK1–IRF3 Signalling Pathway

Sun, 17 May 2026 00:00:00 -0700

Dendritic cells (DCs) detect tumour-released double-stranded DNA (dsDNA) through IFI16 (with IFI204 being its murine homologue), leading to phosphorylation-mediated activation of the STING–TBK1–IRF3 pathway. This cascade induces type I interferon production and facilitates interactions with T cells, thereby enhancing antitumor immunity and suppressing tumour immune escape.

ABSTRACT

IFI16 (the murine homologue is IFI204) is an intracellular double-stranded DNA (dsDNA) pattern recognition receptor (PRR) that plays a crucial role in bridging innate and adaptive immunity. However, its function in dendritic cell (DC) activation and anti-hepatocellular carcinoma (HCC) efficacy remains poorly characterised. This study demonstrates that IFI16 promotes DC maturation, functional activation and antitumor immunity. This effect occurs through activation of the STING–TBK1–IRF3 signalling pathway. Our findings establish IFI16 as a key molecule enabling DCs to sense dsDNA and initiate antitumor responses. Consequently, targeting IFI16 and its downstream STING–TBK1–IRF3 signalling pathway represents a potential therapeutic strategy for hepatocellular carcinoma.

Inducing Antigen‐Specific and Functional Immune Responses in Mice Toward Bovine Herpesvirus 1 and Bovine Respiratory Syncytial Virus by Chimeric Peptides Delivered by Bovine Herpesvirus 4‐Based Vector

Fri, 15 May 2026 08:02:50 -0700

Bovine Alphaherpesvirus 1 (BoHV-1) and Bovine respiratory syncytial virus (BRSV) are major drivers of respiratory disease in cattle. (A) To target both pathogens, two chimeric antigens—membrane-linked and secreted—combining BoHV-1 glycoprotein D and BRSV fusion glycoprotein were designed and expressed using recombinant BoHV-4-based vectors. (B) These constructs induced robust humoral and cellular immunity, including neutralising antibodies and antigen-specific cytotoxic T cells. This strategy represents a promising one health approach with potential applications for controlling related human viruses such as hRSV and VZV.

ABSTRACT

Bovine respiratory disease (BRD) remains a major health and economic challenge for the cattle industry, driven by the interplay of viral and bacterial pathogens that compromise animal welfare, productivity and antimicrobial stewardship. Among the primary viral agents, Bovine herpesvirus 1 (BoHV-1) and Bovine respiratory syncytial virus (BRSV) play critical roles in initiating and exacerbating respiratory pathology. In this study, we engineered two recombinant Bovine herpesvirus 4 (BoHV-4)-based vectors encoding chimeric antigens based on BoHV-1 glycoprotein D (gD) and BRSV fusion glycoprotein (gF), with the goal of developing a multivalent vaccine platform. Immunological evaluation in a murine model demonstrated that both vaccine constructs elicited robust humoral and cell-mediated immune responses directed against both pathogens. Vaccination induced neutralising antibodies capable of inhibiting BoHV-1 and BRSV infection, as well as antigen-specific T-cell responses that mediated cytotoxic activity against target cells expressing either antigen. These findings provide proof-of-concept that chimeric antigens are effective in eliciting humoral and cellular immune response toward two main different pathogens, BoHV-1 and BRSV, and BoHV-4 is a versatile vector for the delivery of heterologous antigens. The demonstrated ability to induce both virus neutralisation and cytotoxic T-cell activity supports the further development of BoHV-4-vectored bivalent vaccines for BRD control, with potential application at improving livestock health and reducing reliance on antimicrobial treatments. Moreover, the present study highlights BoHV-4-based vectors and chimeric peptides as a promising bivalent vaccine platform potentially translatable for controlling similar viruses like human respiratory syncytial virus (hRSV) and varicella zoster virus (VZV) across human populations.

Regulation of Proximal TCR Signalling Requires Wiskott–Aldrich Syndrome Protein

Wed, 13 May 2026 05:06:38 -0700

A model for WASp functions in proximal TCR signalling. Upon TCR ligation, (1) WASp-driven actin polymerisation facilitates the recruitment and interaction of signalling proteins such as Lck and ZAP70 with their binding partners, thereby sustaining TCR signalling. (2) In association with Nck, WASp is recruited to the CD3ε, where they cooperate to stabilise the active conformation of the CD3ε, facilitating access of Lck to the tyrosine residues within the cytoplasmic tails of CD3ε and (3) WASp interacts with Lck and facilitates its translocation to the TCR complex, thereby promoting efficient phosphorylation of Lck substrates such as ZAP70 and CD3 subunits.

ABSTRACT

Wiskott–Aldrich Syndrome protein (WASp) is an actin nucleation-promoting factor that regulates the dynamic rearrangements of the actin cytoskeleton following T cell receptor (TCR) engagement. Recognition of antigen by T cells leads to TCR signal transduction, which involves the phosphorylation of various proteins in close proximity to the TCR, known as proximal TCR signalling. Proximal TCR signalling is initiated by the phosphorylation of signalling proteins including CD3 subunits, lymphocyte-specific protein tyrosine kinase (Lck) and zeta-chain-associated protein kinase 70 (ZAP70). Activation of these proteins initiates the formation of a signalosome, which is required for actin polymerisation and gene expression. The role of WASp in relation to proximal TCR signalling is largely unknown. In the present study, we knocked out WASp in Jurkat T cells using the CRISPR-Cas9 system to evaluate its effect on proximal TCR signalling. As expected, Jurkat T cells lacking WASp exhibited impaired actin polymerisation. Following TCR triggering, phosphorylation of CD3, Lck and ZAP70 was markedly reduced. There was also a failure in the recruitment of Lck and ZAP70 to the TCR. Impaired proximal TCR signalling (reduced tyrosine phosphorylation of CD3, Lck and ZAP70) was exclusively associated with decreased CD69 and CD25 expression. Therefore, besides its role in actin rearrangement, WASp is also required for proximal TCR signalling.

High‐Dimensional Immune Profiling Identifies Circulating NKT‐Like Cells Associated With Severity Outcome in Acute Pancreatitis at Disease Onset

Tue, 12 May 2026 19:06:06 -0700

High-dimensional spectral cytometry of peripheral blood mononuclear cells at hospital admission revealed that acute pancreatitis patients who subsequently developed moderately-to-severe disease exhibited a specific reduction of circulating CD2 + CD8dim NKT-like cells, which appear to acquire an altered cytotoxic-like phenotype upon IL-15 stimulation. Quantifying the phenotype and function of circulating NKT-like cells at admission could therefore serve as an early predictive biomarker of acute pancreatitis severity, enabling risk stratification and personalized treatment.

ABSTRACT

Acute pancreatitis (AP) patients can be classified into mild or severe outcome based on the presence of organ failure days during hospitalization. However, there are no biomarkers that can predict severity outcome. This study aim is to perform an unbiased characterization of the circulating immunome of AP patients at hospital admission aiming to identify novel biomarkers which could predict disease outcome prior to the onset of organ damage and clinical deterioration. Peripheral blood mononuclear cells (PBMC) were collected from newly hospitalized AP patients. Based on their evolution, patients were classified following the Modified Atlanta classification into mild acute pancreatitis (mAP) (n = 20) as well as moderately and/or severe acute pancreatitis (ms-sAP) (n = 20). PBMC were analysed by high-dimensional spectral cytometry with unsupervised dimensionality reduction and clustering algorithms based on the subsequent outcome of the patients. Results were further validated by classical gating and functional approaches with a smaller cohort (n = 8 mAP and n = 8 ms-sAP). A total of 120 different immune cell clusters were identified and characterized in AP patients at hospitalization. Following computational analysis and classical gating validation approaches, circulating CD2⁺CD8^dim NKT-Like cells were found to be specifically reduced in ms-sAP patients. Moreover, NKT-Like cell subsets from these patients displayed an IL-15 induced expansion of NKG2a and NKp30 referred to mAP. Patients with AP at hospitalization with subsequent ms-sAP display a specific reduction of NKT-Like cells coupled with an expanded function. Hence, quantifying the phenotype and/or function of circulating NKT-Like cells during hospital admission could serve as a predictive biomarker for AP severity, aiding in early stratification and personalized treatment strategies.

The Potential Function of Toxoplasma gondii in Tumour Immunotherapy

Sun, 10 May 2026 21:44:28 -0700

Remodelling of the tumour microenvironment (TME): T. gondii and its derivatives. Treatment with Toxoplasma gondii or its derivatives reprograms an immunosuppressive TME into a more immunostimulatory state in tumour models. It reduces both the abundance and suppressive activity of key immunoregulatory populations within the TME, including tumour-associated macrophages (TAMs), myeloid-derived suppressor cells (MDSCs), and regulatory T cells (Tregs), while diminishing inhibitory cytokines such as interleukin-6 (IL-6), Interleukin-10 (IL-10), and Transforming Growth Factor-β (TGF-β). Concurrently, it promotes dendritic cell (DC) activation, drives macrophage polarisation toward an M1 phenotype, and enhances antitumor immunity by activating natural killer (NK) cells, CD4⁺ T cells, and cytotoxic CD8⁺ T cells, including granzyme B⁺ effector CD8⁺ T cells. These changes strengthen the IL-12/IFN-γ axis, increase IL-12, tumour necrosis factor-α (TNF-α), and IFN-γ and induce a Th1-type imuune response that may promote immunologically ‘cold’ tumours a more inflamed ‘hot’ state. Beyond immune remodelling, T. gondii and its derivatives may also exert direct antitumor effects by inducing tumour-cell apoptosis, potentially through activation of p53 signalling and reinforcement of PTEN-mediated tumour-suppressive pathways, together with reduced Bcl-2 and increased Bax, Bak, cytochrome c, and caspase-3. In addition, they can trigger cell-cycle arrest and inhibit angiogenesis by downregulating proangiogenic factors such as CD31, vascular endothelial growth factor (VEGF), and TGF-β. T. gondii-based interventions may further limit metastasis by suppressing matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9) and modulating tissue inhibitor of metalloproteinase-1 (TIMP-1), thereby restricting ECM remodelling and reducing tumour-cell invasiveness.

ABSTRACT

Immunotherapy has revolutionised the clinical treatment of many types of cancer, including immune checkpoint inhibitors, adoptive cell therapies, and tumour vaccines, which are capable of providing long-term clinical benefit in some patients. Nevertheless, a high degree of tumour immune heterogeneity and an ongoing immunosuppressive the tumour microenvironment (TME) remain as limitations to therapeutic outcomes, and alternative methods to stimulate antitumor immunity are necessary. Given these limitations, recent researchers has been attracted to the fact that Toxoplasma gondii and its derivatives can be considered as unconventional parasite-derived immunomodulatory vectors in cancer immunotherapy. T. gondii infection triggers strong Th1 immunity mediated on interleukin-12 (IL-12) and interferon-γ (IFN-γ), promotes dendritic cell maturation, and activates cytotoxic T cells, thus reprogramming the TME to a more immunostimulatory condition. Attenuated or metabolic-deficient strains have shown strong antitumor efficacy in various murine tumour models by reducing tumour burden and prolonging host survival. Meanwhile, the effector proteins of the parasite, such as GRA15, GRA16, and ROP18, regulate immune cell function to induce tumour cell apoptosis, inhibit angiogenesis, and suppress metastasis. The T. gondii-infected cell-derived exosomes and T. gondii lysate antigens are also immunogenic and represent safer, non-infectious therapeutic alternatives. Here, we summarise the latest advances in the antitumor effects of T. gondii and its derivatives, focusing on immune activation, signalling regulation, direct antitumor effects, synergistic immunotherapy, potential for drug development, and challenges in future clinical translation. T. gondii and its derivatives have shown the potential to reshape TME and convert ‘cold’ tumours into ‘hot’ ones in murine cancer models. We believe that with further research in this field, the future of cancer immunotherapy will see breakthrough advancements.

Benchmarking Dendritic Cell Enrichment Methods Reveals Subset‐Specific Recovery Biases

Sat, 09 May 2026 02:14:33 -0700

Dendritic cells (DCs) are rare in human blood, often requiring enrichment prior to analysis. Here, we benchmark commonly used pan-DC enrichment methods by comparing recovered DC subset composition to ex vivo references. While all approaches capture major DC populations, recovery is partial and exhibits method-dependent, subset-specific biases. These differences alter the apparent DC composition and may influence downstream analyses. Created with BioRender.com.

Novel Pathway for Intercepting Granular Exocytosis: A13 Engages APLNR to Drive FBXO28‐Mediated Ubiquitination and Proteasomal Clearance of Rab27a in Allergic Inflammation

Fri, 01 May 2026 22:28:15 -0700

A13 binds to APLNR on mast cells/eosinophils, triggering recruitment of the E3 ubiquitin ligase FBXO28. FBXO28 mediates K48-linked polyubiquitination of Rab27a, leading to its proteasomal degradation. This process blocks granular exocytosis of pro-allergic mediators (EPX, Mcpt1, histamine), attenuates Th2 cytokine production and sIgE levels, and restores Th1/Th2 immune balance, ultimately suppressing allergic airway inflammation with localised action and no systemic immunosuppression.

ABSTRACT

Allergic airway inflammation (AA) is primarily driven by the activation of mast cells and eosinophils, with granular exocytosis serving as a key source of pro-allergic mediators that amplify pathological responses. This unmet need highlights the importance of identifying novel, pathway-specific therapeutic targets to improve disease management. A dust mite extract (DME)-induced murine model of AA was used to assess intranasal A13 (1 mg/kg daily) efficacy; human EoL-1 eosinophils and murine P815 mast cells were stimulated with PMA/ionomycin (P&I) to induce exocytosis. In DME-induced murine AA, intranasal A13 reduced lung inflammation by 58% (p < 0.01), serum sIgE by 73% (p < 0.001), and BALF Th2 cytokines (IL-4/IL-5/IL-13) by 65%–80% (p < 0.001), while restoring BALF IFN-γ (p < 0.01). A13 inhibited granular mediator release: in P&I-challenged WT mice, it reduced BALF eosinophil peroxidase (EPX) by 81% and mast cell protease-1 by 85%, but had no effect in APLNR⁻^/⁻ mice (p > 0.05). Mechanistically, P&I induced Rab27a upregulation (P815: 3.2-fold; EoL-1: 2.8-fold), which A13 reversed in vitro; in vivo, A13 lowered lung granulocyte Rab27a by 2.5–3.1-fold (p < 0.001). A13 engaged APLNR to recruit FBXO28, promoting K48-linked Rab27a ubiquitination and proteasomal degradation. APLNR knockdown or MG132 treatment abrogated A13's effects, while A13 enhanced FBXO28-Rab27a complex formation by 4.7-fold (p < 0.001)—an interaction undetectable in APLNR^−/− cells. Intranasal A13 exhibits localised action, effectively suppressing allergic inflammation without broad systemic immunosuppression, making it a promising candidate for development as a topical biologic to treat allergic airway diseases.

Natural Killer Cell‐Based Immunotherapy in HCC

Linlin Che, Xueting Xie, Xiaoyu Yang, Shiguo Zhu, Yufu Zhou — Tue, 28 Apr 2026 02:38:29 -0700

This review systematically examines seven major strategies for NK cell-based immunotherapy in Hepatocellular carcinoma (HCC), including adoptive transfer, genetic engineering, checkpoint blockade, TME reprogramming, cytokine enhancement, TCM modulation, and combination approaches. By linking specific mechanisms of NK cell dysfunction to corresponding therapeutic interventions and summarizing current clinical trial outcomes, we highlight that rational multi-targeted combinations, rather than monotherapy, will be essential to overcome the multifaceted immunosuppression in HCC and achieve durable clinical responses.

ABSTRACT

Hepatocellular carcinoma (HCC) poses a formidable therapeutic challenge due to its high heterogeneity, frequent late-stage diagnosis, and chemoresistance. Natural killer (NK) cells are essential for immune surveillance, yet their quantity and function become significantly compromised during HCC progression, thereby promoting tumour immune escape. This review systematically outlines current NK cell-based immunotherapeutic strategies for HCC, including adoptive NK cell transfer, genetic engineering of NK cells, NK cell inhibitory receptor-targeted therapies, reprogramming of the immunosuppressive HCC microenvironment, cytokine-mediated enhancement of NK cell function, and traditional Chinese medicine-augmented NK cell cytotoxicity. Representing a promising immunotherapeutic paradigm, NK cell-based therapy is rapidly advancing from conventional cell infusion toward more precise modalities, including CAR-NK cells and multifunctional antibody engagers. However, the efficacy of these approaches is frequently curtailed by the immunosuppressive tumour microenvironment and tumour heterogeneity. Given the multifactorial nature of NK cell dysfunction, we highlight that rationally designed combination strategies-integrating genetic engineering, TME reprogramming, and checkpoint blockade-represent the most viable path toward durable clinical responses in HCC.

Dual Functions of Treg in the Mucosal Barrier and Lung Cancer Microenvironment and Prospects for Targeted Therapy

Mon, 27 Apr 2026 01:21:53 -0700

Regulatory T cells exhibit a dual role: maintaining mucosal barrier homeostasis in healthy lung tissue, while driving immune escape in the lung cancer microenvironment. This functional shift is mediated by forming an immunosuppressive network that potently suppresses effector T cells. Understanding this transition provides critical insights for targeting Tregs in lung cancer immunotherapy.

ABSTRACT

Lung cancer remains one of the most common and deadly malignancies worldwide, representing a process intimately associated with dynamic changes in the tumour immune microenvironment. The pulmonary mucosal barrier, which serves as the first line of immune defence against pathogens and exogenous insults, not only restrains excessive inflammation by preserving local immune homeostasis but also actively participates in shaping the lung cancer microenvironment. Regulatory T cells (Tregs) are critical immunosuppressive cells that play a dual role in this context: they sustain immune tolerance by supporting mucosal barrier integrity and preventing autoimmunity, while concurrently mediating immunosuppression within the tumour niche to facilitate immune evasion and disease progression. Although recent years have seen considerable progress in elucidating the roles of the mucosal barrier and Tregs in lung cancer, their molecular regulatory networks and translational potential as therapeutic targets require further systematic investigation. This review synthesises current understanding of the interplay between the mucosal barrier and Tregs in the lung cancer immune microenvironment, with a focus on the functional balance between Treg-mediated immunosuppression and mucosal maintenance. Based on this, we propose an integrative conceptual framework—the “mucosal-Treg-tumor immune axis”—to reconcile the context-dependent duality of Tregs. It also evaluates current strategies and clinical prospects for targeting Tregs and associated signalling pathways in lung cancer immunotherapy, aiming to offer novel perspectives for therapeutic optimisation.

Precision Glyco‐Modulated GcMAF2.0 Targets CLEC10A to Bidirectionally Re‐Wire Macrophage States: Cross‐Species Evidence, Mechanistic Omics and Translational Horizons

Thu, 19 Mar 2026 07:51:16 -0700

This graphical abstract summarises how precision glyco-editing of vitamin D-binding protein generates defined GcMAF2.0 variants that expose a single α-GalNAc epitope, engage the macrophage lectin CLEC10A, and bias signalling towards either pro-inflammatory (EF-M1) or pro-resolving (EF-M2) states. Cross-species in vitro, in vivo and mesoscopic data, together with early clinical observations, support this CLEC10A-centred axis as a tractable route for rational macrophage re-programming in inflammatory, degenerative and malignant disease.

ABSTRACT

Macrophages orchestrate inflammation, tissue repair and tumour surveillance, yet macrophage-targeted strategies such as CSF1R inhibition, CD47 blockade or TLR7/8 agonists have so far yielded only modest, context-restricted benefit. The C-type lectin CLEC10A (MGL/CD301) recognises a single terminal α-N-acetylgalactosamine (α-GalNAc) and couples this minimalist glycan cue to context-dependent inflammatory or reparative programmes, making it an attractive target for precision macrophage re-programming. This review synthesises mechanistic, pre-clinical and clinical data on Gc protein-derived macrophage-activating factor 2.0 (GcMAF2.0), a mono-α-GalNAc derivative of vitamin-D-binding protein that engages CLEC10A with high avidity. We summarise lessons from heterogeneous “GcMAF1.0” products, outline GMP workflows that yield EF-M1/EF-M2, and review CLEC10A-centred signalling and metabolic re-wiring, including SYK versus STAT6/PPARγ cascades and shifts in arginine, glucose and fatty-acid metabolism. Cross-species data from rodent inflammation models, human and canine myeloid cells, barrier-tissue and tumour models, and mesoscopic platforms indicate that α-GalNAc ligands and EF-M2 bias macrophage profiles and attenuate joint and barrier-tissue inflammation. A randomised double-blind placebo-controlled trial of EF-M2 in canine osteoarthritis links macrophage repolarisation to pain relief, gait restoration and serum ARG1/iNOS and IL-10/TNF-α shifts, providing disease-modifying proof of concept. We also review the small, uncontrolled human experience with analytically characterised GcMAF2.0 (≈120 patient-courses), noting favourable short-term tolerability but low certainty of benefit and a need for randomised, lot-traceable trials with mechanistic endpoints. Overall, we position the α-GalNAc–CLEC10A axis as a tunable handle on macrophage plasticity and outline the experimental and regulatory priorities needed to translate GcMAF2.0 into evidence-based immunotherapy.

Inside Out: How Cellular Localisation Shapes cGAS Functions in Health and Disease

Jiaqi Wu, Yingying Zhou, Bo Zeng, Yuan Wang, Chenhui Wang — Wed, 18 Mar 2026 08:31:52 -0700

cGAS, a central innate immune sensor, executes context-specific functions based on its subcellular address. A dynamic ‘location code’—governed by PTMs, protein interactions, and membrane binding—directs cGAS to compartments including the nucleus, mitochondria, and micronuclei, where it enacts discrete programs in antiviral defence, genome integrity, and metabolic stress response. This spatial logic explains its dual roles in immunity and pathology, offering a framework for compartment-specific therapeutic targeting.

ABSTRACT

The function of innate immune sensors is intricately shaped by their spatial distribution within cells. cGAS (cyclic GMP-AMP synthase), a key cytosolic DNA sensor, illustrates this principle through its unexpected localisation to diverse organelles—including the nucleus, micronuclei, mitochondria, and plasma membrane. In these compartments, cGAS assumes distinct regulatory states and executes specialised functions. For instance, chromatin-bound nuclear cGAS remains inactive under homeostasis but contributes to genome maintenance during genotoxic stress, whereas mitochondrial or micronuclear cGAS links damage signals to inflammation and cell death. This review synthesises recent advances in the spatial regulation of cGAS, focusing on mechanisms such as membrane interactions and post-translational modifications. We further reframe cGAS as a multifunctional regulator in infection, cancer, autoimmunity, and ageing, and introduce a unifying ‘location code’ framework. This framework proposes that the combined influence of PTMs, protein interactions, and membrane affinities dictates cGAS localisation, functional output, and pathological outcomes, thereby paving the way for spatially informed therapeutic interventions.

Bruton's Tyrosine Kinase—Going Beyond the B Cell

Rochelle Y. Benoit, Sheila Loshi, Craig S. Moore — Thu, 26 Feb 2026 02:33:00 -0800

This graphical abstract summarises the pleiotropic immunomodulatory effects of Bruton's tyrosine kinase (BTK) inhibition across innate immune cell populations and disease contexts. BTK inhibition can target multiple myeloid-lineage cells, including microglia, Kupffer cells, osteoclasts, granulocytes, and circulating monocytes.

ABSTRACT

Bruton's Tyrosine Kinase (BTK) is a cytoplasmic kinase essential for B cell-mediated signalling, yet has also received recent recognition as a direct regulator of myeloid cell function. Beyond its established role in B cell malignancies, BTK influences receptor-driven activation in monocytes, macrophages, microglia, granulocytes, and other organ-specific macrophages by influencing key molecular pathways involved in phagocytosis, inflammatory-mediated signalling, and cell metabolism (e.g., NFκB, STAT3, and NLRP3). BTK inhibitors (BTKis) were initially developed and approved to treat B cell-related cancers, however, they have also demonstrated significant therapeutic/clinical efficacy in autoimmune, allergic, and immune-driven neuroinflammatory disorders, including rheumatoid arthritis, IgA nephropathy, multiple sclerosis, and chronic spontaneous urticaria. This review specifically addresses, compares, and summarises how BTK inhibition within distinct myeloid-derived cell subsets alters inflammatory-related phenotypes and functions within these cells. Together, providing cell-specific insights into BTK as a central regulator of innate immunity and myeloid cell function may help generate significant translational potential for BTKis in multiple inflammatory-mediated diseases.

BXSB.Yaa: A Translational Model of Toll‐Like Receptor 7‐Type I Interferon‐Driven Systemic Lupus Erythematosus

Mon, 02 Feb 2026 16:52:42 -0800

The BXSB.Yaa mouse model demonstrates how increased Toll-like receptor 7 activity drives a type I interferon–dominated immune cascade that links innate immune activation to B- and T-cell dysregulation, autoantibody production, and multi-organ pathology characteristic of systemic lupus erythematosus. This model closely mirrors key clinical and immunological features of human lupus, establishing BXSB.Yaa as a powerful translational platform for studying disease mechanisms and testing interferon- and TLR7-targeted therapies.

ABSTRACT

Despite recent approvals of belimumab and anifrolumab, durable, steroid-sparing remission in systemic lupus erythematosus (SLE) remains uncommon, underscoring ongoing therapeutic needs. The BXSB.Yaa mouse model, harbouring Y-linked Tlr7 duplication on a polygenic susceptibility background, has been instrumental in elucidating the TLR7–type I interferon (IFN1) axis central to SLE. This review positions BXSB.Yaa as a comparative model system and advances a mechanism-aligned framework that maps murine models to human SLE endotypes (e.g., IFN1-high vs. IFN-γ-dominant; germinal center- vs. extrafollicular-biased B-cell responses) and links those endotypes to targeted interventions. We highlight the fidelity of BXSB.Yaa to IFN1-high patient biology, and its contributions of polygenic susceptibility in driving immune cell dysregulation, cytokine imbalance, and therapeutic responsiveness to BAFF and IFN1 blockade. Notably, this model also recapitulates pathogenic pDC activation, highlighting its relevance for emerging pDC-targeted strategies. By contrasting BXSB.Yaa with other prominent lupus-prone strains (e.g., MRL/lpr, NZBWF1, NZM2410, B6.SLE1/2/3, BXD2, and Kika), we benchmark its predictive value for clinical heterogeneity and treatment response. We synthesise insights from BXSB.Yaa studies, including those that informed FDA-approved biologics, and discuss implications for next-generation precision therapies. Collectively, we advocate for BXSB.Yaa as an essential pre-clinical platform among complementary models to accelerate mechanism-based drug development and enable stratified translation in SLE research.

COX‐2 Mediates Immune Evasion and Decreases Chemosensitivity in Breast Cancer Through Activation of the JAK2/STAT3 Signalling Pathway

Sat, 06 Sep 2025 00:50:51 -0700

In our study, we confirmed that COX-2 was highly expressed in breast cancer. COX-2 promoted the malignant progression of breast cancer cells through the JAK2/STAT3 signalling pathway, thereby facilitating immune evasion and reducing sensitivity to chemotherapeutic drugs.

ABSTRACT

With 1 in every 20 women afflicted, breast cancer is the most frequent malignant tumour in women and a significant health burden on women. Drug resistance in cancer is the key problem limiting current therapy approaches. Cyclooxygenase-2 (COX-2, namely PTGS2) is linked to immune evasion and chemoresistance in tumour cells, and it is frequently overexpressed in many forms of cancer. It is currently unclear how precisely this regulatory link functions in breast cancer, though. COX-2 expression in breast cancer was verified by this investigation. COX-2 knockdown was used to confirm COX-2 function in the malignant development of tumour cells and the stimulation of the JAK2/STAT3 signalling pathway. The survival of tumour cells was then assessed by co-culturing with CD8⁺ T cells or receiving chemotherapy after COX-2 was knocked down. To examine the function of the JAK2/STAT3 signalling system, cells from each group were then treated with a combination of COX-2 overexpression plasmid and JAK2/STAT3 inhibitor. The tissues and cells of breast cancer had elevated expression levels of COX-2. Following the downregulation of COX-2, breast cancer cells showed enhanced apoptosis, lower susceptibility to chemotherapy, impeded proliferation and epithelial–mesenchymal transition and were more readily destroyed by CD8⁺ T lymphocytes. Nevertheless, the opposite effects were shown when COX-2 was overexpressed, and JAK2/STAT3 inhibitors were able to reverse these effects. COX-2 activated the JAK2/STAT3 signalling pathway, which in turn promoted immune evasion and decreased chemosensitivity in breast cancer.

Microneedle‐Delivered Multivalent MPXV DNA Vaccines Induce Promising Immunity Profiles and Cross‐Protection in Mice

Tue, 02 Sep 2025 16:29:57 -0700

Multivalent MPXV DNA vaccines encoding IMV and EEV antigens, delivered via dissolvable microneedle array patches (D-MAPs), elicited strong humoral and T cell responses and conferred robust protection against lethal VACV-WR challenge in mice. The immunogenicity induced by D-MAP delivery was comparable to that of intramuscular electroporation (IM-E) and the M3 and M4 formulations achieved protective efficacy similar to the traditional replication-competent smallpox vaccine TianTan (VTT). These findings highlight D-MAP as a minimally invasive, field-deployable platform for mpox vaccination, offering a promising alternative for enhancing immune protection against MPXV and other orthopoxviruses.

ABSTRACT

Traditional DNA vaccines, typically administered via intramuscular injection with electroporation (IM-E), often cause discomfort and require trained personnel. Addressing these challenges, we developed multivalent DNA vaccines targeting both intracellular mature virion (IMV) and extracellular enveloped virion (EEV) proteins of the monkeypox virus (MPXV), designated as M2 (A29L, B6R), M3 (A29L, B6R, M1R) and M4 (A29L, B6R, M1R, A35R). These vaccine constructs were formulated into dissolvable microneedle array patches (D-MAPs) for intradermal delivery. Comparative studies in mice demonstrated that D-MAPs achieved approximately 70% delivery efficiency and elicited robust humoral immune responses in mice, including antigen-specific IgG and cross-neutralising antibodies against MPXV, VACV and ECTV—comparable to those induced by IM-E. Furthermore, D-MAP immunisation induced stronger T cell responses, particularly in the draining lymph nodes. Importantly, the multivalent DNA vaccines—especially M3 and M4—conferred substantial protection against lethal VACV-WR challenge, achieving levels of protection comparable to the traditional replication-competent smallpox vaccine TianTan (VTT), with significant viral suppression and mitigation of pathological damage. Collectively, this study provided valuable insights for the development of innovative MPXV DNA vaccines, highlighting a minimally invasive and suitable for field application with D-MAP with broad potential for combating mpox outbreaks and future orthopoxvirus pandemics.

Dendritic Cell‐Derived Extracellular Vesicles as Therapeutic Cancer Vaccines: Mechanisms and Optimization Strategies

Jonathan Shpigelman, Krishna Rao — Tue, 02 Sep 2025 00:00:00 -0700

Extracellular vesicles (EVs) can contribute to antigen presentation indirectly, semi-directly, or directly. The latter two mechanisms rely on functional peptide–major histocompatibility (pMHC) complexes on EVs, bypassing the need for independent antigen processing by antigen-presenting cells. Dendritic cell-derived EVs are enriched in pMHC complexes and other immunostimulatory cargo, enabling them to participate in these unique modes of antigen presentation and positioning them as promising cancer vaccine platforms. Realising their full potential, however, will require prioritising tumour-specific antigens, incorporating adjuvants, optimising EV production and delivery, and applying tailored engineering strategies.

ABSTRACT

Extracellular vesicles (EVs) are ubiquitously secreted nanoparticles that modulate the activities of recipient cells either through the transfer of bioactive cargo or by surface receptor-mediated signalling. EVs derived from dendritic cells are increasingly recognised as promising platforms for therapeutic cancer vaccines, owing to their immunostimulatory cargo, their capacity to transfer preformed peptide–major histocompatibility complexes to antigen-presenting cells, and their ability, in some cases, to directly activate cognate T cells. Despite encouraging preclinical results, EV-based cancer vaccines have demonstrated limited clinical efficacy, constrained by suboptimal immunogenicity, poor lymphoid targeting, and suppression within the tumour microenvironment. Several strategies—including prioritising tumour-specific neoantigens, co-administering adjuvants and immunotherapies, optimising EV production and delivery protocols, and engineering EVs with tailored characteristics—aim to overcome these limitations and improve clinical outcomes.

Tissue Resident Memory Cells: Friend or Foe?

Chidimma F. Chude, Jude E. Uzonna, Janilyn Arsenio — Sun, 03 Aug 2025 21:24:25 -0700

Tissue-resident memory T cells (T_RM cells) are specialised immune cells in barrier tissues like the lungs, skin and gut, providing rapid host defence and tumour surveillance. Their retention and differentiation are regulated by molecules such as CD69, CD103 and TGF-β. Dysregulation of T_RM cells can lead to chronic activation, driving conditions such as psoriasis, asthma and IBD. Therapeutic approaches include metabolic reprogramming to enhance antitumour functions, nanodrug delivery systems for targeted modulation, and immune interventions like checkpoint inhibitors and cytokine modulation. These strategies aim to harness T_RM cells' protective roles while mitigating their pathogenic potential, offering new avenues for disease management. Image created in Biorender.

ABSTRACT

Tissue-resident memory T (T_RM) cells are a specialised subset of immune cells that remain within tissues, playing a vital role in localised immune defence and long-term immunity. Unlike circulating memory T cells, T_RM cells do not recirculate to provide rapid and effective responses against previously encountered pathogens at the tissue level. The formation of T_RM cells is driven by tissue-specific cues, guiding their differentiation and retention within organs such as the skin, lungs and gut. They are characterised by the expression of unique markers, including CD69 and CD103, which facilitate their retention and longevity in tissues. T_RM cells are essential for immune surveillance, effectively detecting and responding to different infections and contributing to tumour suppression. However, T_RM cells are also implicated in chronic inflammatory and autoimmune diseases, where persistent activation by resident and autoantigens can lead to tissue damage. This pathogenic role is evident in chronic inflammatory conditions such as psoriasis, vitiligo and inflammatory bowel disease (IBD), where T_RM cells may drive persistent localised inflammation and contribute to disease progression and severity. Emerging therapeutic strategies seek to modulate T_RM cells to balance their protective and pathogenic roles in these inflammatory diseases. Approaches such as checkpoint inhibitors, cytokine modulation and cell-depletion therapies aim to enhance T_RM cells' beneficial immune functions while minimising their role in autoimmunity. A deeper understanding of T_RM cell development, maintenance and functional diversity is critical for advancing treatments for infectious diseases, chronic inflammation, autoimmune conditions and cancer.

Tertiary Lymphoid Structures: Allies of Cancer Immunotherapy

Thu, 24 Jul 2025 02:51:49 -0700

Tertiary lymphoid structures indicate a positive response to cancer immunotherapy by generating high-affinity antibodies and activating T cells to recognise and eliminate tumour cells.

ABSTRACT

Immunotherapy has demonstrated groundbreaking clinical efficacy across diverse cancer types. Nevertheless, its therapeutic potential remains constrained, with only a small subset of patients achieving durable clinical responses. Emerging evidence highlights tertiary lymphoid structures (TLSs), ectopic lymphoid aggregates induced by chronic inflammation or malignancy, play critical roles in mediating positive responses to cancer immunotherapy. Currently, there is a notable absence of comprehensive systematic evaluations that synthesise both clinical and preclinical experimental data regarding the role of TLSs in enhancing cancer immunotherapy. In this review, we examined the composition of TLSs and elucidated how their heterogeneity influences cancer treatment outcomes, with implications for both clinical practice and translational research. Furthermore, we emphasised the role of T follicular helper cells–mediated positive selection of germinal centre B cells in driving high-affinity antibody production. Additionally, we comprehensively analysed the effects of pharmacological agents, oncolytic viruses, adeno-associated viruses and biomaterials on TLSs formation and highlighted their capacity to potentiate immune checkpoint inhibitor responses. Consequently, targeting TLSs is a promising strategy for enhancing the positive response to cancer immunotherapy.

Induction of Regulatory T Cells After Virus Infection and Vaccination

MansourehKarimi Kakh, Mehrnoosh Doroudchi, AtefeGhamar Talepoor — Wed, 07 May 2025 00:38:07 -0700

The representation of the Tregs immune responses after viral infection and viral vaccination. (A) After viral infection, Treg can limit excessive immune activation and tissue damage by different mechanisms. These include the secretion of regulatory cytokines, the expression of inhibitory receptors such as cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and lymphocyte-activation gene 3 (LAG-3), as well as cell-contact-dependent inhibition of effector T cells. Moreover, Treg contributes to tissue repair through the production of amphiregulin. (B) After viral vaccination, Tregs play a critical role in controlling or limiting vaccine-induced immunity. Tregs secrete anti-inflammatory cytokines IL-10, TGF-β and IL-35 and induce apoptosis of effector T cells by granzyme generation. Tregs also express CTLA-4, which binds CD80 and CD86 expressed on antigen presenting cells (APCs), mediating the suppression of dendritic cell (DC) maturation and presentation of antigens to effector T cells.

ABSTRACT

Vaccines have been proven to be one of the safest and most effective ways to prevent and combat diseases. However, the main focus has been on the evaluation of the potency of effector mechanisms and the lack of adverse effects of vaccine candidates. Recently, the importance of induced regulatory mechanisms of the immune system after vaccination has come to light. With the increase in our knowledge about these regulatory mechanisms including the regulatory T cells (Tregs), we have come to understand the significance of this arm of the immune system in controlling immunopathology and/or diminishing the effectiveness of vaccines, especially viral vaccines. Tregs play a dual role during infectious diseases by limiting immune-mediated pathology and also contributing to chronic pathogen persistence by decreasing effector immunity and clearance of infection. Tregs may also affect immune responses after vaccination primarily by inhibiting antigen presenting cell function such as cytokine secretion and co-stimulatory molecule expression as well as effector T (Teff) and B cell function. In this article, we review the current knowledge on the induction of Tregs after several life-threatening virus infections and their available vaccines to bring them to the spotlight and emphasise that studying viral-induced antigen-specific Tregs will help us improve the effectiveness and decrease the immunopathology or side effects of viral vaccines.

Trial Registration: ClinicalTrials.gov identifier: NCT04357444

SAA1 as a Potential Early Diagnostic Biomarker for Sepsis Through Integrated Proteomics and Metabolomics

Thu, 10 Apr 2025 18:21:55 -0700

This study compared sepsis patients and healthy individuals, identifying and validating serum amyloid A1 (SAA1) as a diagnostic biomarker through non-targeted and targeted proteomics and metabolomics sequencing, combined with various analytical methods. The results demonstrated that SAA1 had high diagnostic value (AUC = 0.95) and could serve as a potential biomarker for early sepsis detection.

ABSTRACT

Sepsis is characterised by fatal organ dysfunction resulting from a dysfunctional host response to infection, imposing a substantial economic burden on families and society. Therefore, identifying biomarkers for early sepsis diagnosis and improving patient prognosis are critical. This study recruited 59 sepsis patients and 35 healthy volunteers from the Department of Critical Care Medicine at Harbin Medical University Affiliated First Hospital between March and December 2021. Through a combination of non-targeted and targeted proteomics and metabolomics sequencing, along with various analytical methods, we initially identified and validated serum amyloid A1 (SAA1) as a diagnostic biomarker for sepsis. Our study found that SAA1 was significantly elevated in the sepsis group, demonstrating its diagnostic value for sepsis (AUC: 0.95, 95% CI: 0.88–1). Additionally, a positive correlation was observed between SAA1 and disease severity, as indicated by the Sequential Organ Failure Assessment (SOFA) score (R = 0.51, p = 0.004) and Acute Physiology and Chronic Health Evaluation II (APACHE II) score (R = 0.52, p = 0.003). This study suggests that SAA1 is a potentially effective and reliable marker for diagnosing sepsis and predicting its severity.

Innate Immune Activation Is a Strong Suppressor of CCL22 and Impedes Regulatory T Cell–Dendritic Cell Interaction

Wed, 26 Mar 2025 02:40:16 -0700

During homeostasis, CCL22 is secreted by dendritic cells (DC), which mediate contacts between regulatory T cells (Treg) and DC to maintain immune balance. Activation of innate immunity via microbes or pattern recognition receptor (PRR) agonists induces the secretion of several soluble factors (e.g., type I and II interferons, IL-10), which mediate CCL22 suppression in DC, thereby reducing Treg–DC contact formation. This mechanism might dampen immune suppression in the context of microbial infection to enable effective pathogen clearance.

ABSTRACT

The chemokine CCL22 is constitutively expressed at high levels in lymphoid organs, where it controls immunity by promoting contacts between dendritic cells (DC) and regulatory T cells (Treg). However, its regulation and impact in the context of pattern recognition receptor (PRR) stimulation and microbial infection are unknown. Here we show that CCL22 levels in lymphoid organs of mice were strongly suppressed upon stimulation with TLR agonists. In vitro, activation of Toll-like receptors (TLR), RIG-I like helicases (RLH) and stimulator of interferon genes (STING) resulted in a potent downregulation of CCL22. Mechanistically, the suppression of DC-derived CCL22 secretion was exerted by inflammatory cytokines such as IFN-α, IFN-γ and IL-10 released upon TLR activation by B and T cells. Decreased CCL22 synthesis correlated with reduced frequencies of cellular clustering between Treg and DC in co-cultures. CCL22 suppression was also observed upon microbial infection, since CCL22 levels were significantly reduced in lymphoid organs of mice upon injection of Salmonella typhimurium. As a clinical correlate, CCL22 serum concentrations were decreased in patients with sepsis compared to controls. Taken together, we demonstrate a strong and long-lasting suppression of CCL22 as a consequence of innate immune activation. In the context of microbial infection, transient reduction of CCL22 reduces Treg-DC interactions and may thereby represent a mechanism to weaken Treg function in order to enable an effective immune response and pathogen clearance.

Successful Treatment of Chronic Rhinosinusitis With Nasal Polyps (CRSwNP) With Tezepelumab: A Case Report

Sun, 02 Mar 2025 17:14:32 -0800

Immunology, EarlyView.

Cellular metabolism modulation in T lymphocyte immunity

Mon, 19 May 2014 00:00:00 -0700

Abstract

T lymphocytes are a central component, and play an important role in controlling immunity and immunological diseases. Recent studies have shown that T cell metabolism is highly dynamic and has a tremendous impact on the modulation of T lymphocyte immunity. Specific metabolic pathways meet energy and biosynthetic requirements that can support specific T cell functional activities in immunity and immunological diseases. This review summarizes the recent progresses about the modulatory role of cell metabolism in T cell development, differentiation, activation and function in immunity. These might provide new opportunities to modulate the immune responses and treat clinical immunological diseases.