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Innate Lymphoid Cell Development: A T Cell Perspective

19 June 2018

Publication date: 19 June 2018
Source:Immunity, Volume 48, Issue 6

Author(s): Dylan E. Cherrier, Nicolas Serafini, James P. Di Santo

Innate lymphoid cells (ILCs) and natural killer (NK) cells have garnered considerable interest due to their unique functional properties in immune defense and tissue homeostasis. Our current understanding of how these cells develop has been greatly facilitated by knowledge of T cell biology. Models of T cell differentiation provided the basis for a conceptual classification of these innate effectors and inspired a scheme of their activation and regulation. In this review, we discuss NK cell and ILC development from a “T cell standpoint” in an attempt to extend the analogy between adaptive T cells and their innate ILC and NK cell counterparts.

Teaser

An extended family of innate lymphoid cells (ILCs) and natural killer (NK) are proposed to represent “innate” versions of adaptive helper and cytotoxic T cells, respectively. Here, Di Santo and colleagues examine the developmental lifestyles of ILCs and NK cells through the lens of the well-known T cell differentiation pathways.

Innate Lymphoid Cells: Diversity, Plasticity, and Unique Functions in Immunity

19 June 2018

Publication date: 19 June 2018
Source:Immunity, Volume 48, Issue 6

Author(s): Marco Colonna

Type 1, 2, and 3 innate lymphoid cells (ILCs) have emerged as tissue-resident innate correlates of T helper 1 (Th1), Th2, and Th17 cells. Recent studies suggest that ILCs are more diverse than originally proposed; this might reflect truly distinct lineages or adaptation of ILCs to disparate tissue microenvironments, known as plasticity. Given that ILCs strikingly resemble T cells, are they redundant? While the regulation, timing, and magnitude of ILC and primary T cell responses differ, tissue-resident memory T cells may render ILCs redundant during secondary responses. The unique impact of ILCs in immunity is probably embodied in the extensive array of surface and intracellular receptors that endow these cells with the ability to distinguish between normal and pathogenic components, interact with other cells, and calibrate their cytokine secretion accordingly. Here I review recent advances in elucidating the diversity of ILCs and discuss their unique and redundant functions.

Teaser

Innate lymphoid cells (ILCs) are tissue-resident correlates of T helper 1 (Th1), Th2, and Th17 cells. Colonna reviews recent advances in understanding ILC diversity and functional plasticity—their unique and redundant functions, receptor repertoires, and regulation of gene-expression programs.

HIV-1 Vaccines Based on Antibody Identification, B Cell Ontogeny, and Epitope Structure

15 May 2018

Publication date: 15 May 2018
Source:Immunity, Volume 48, Issue 5

Author(s): Peter D. Kwong, John R. Mascola

HIV-1 vaccine development has been stymied by an inability to induce broadly reactive neutralizing antibodies to the envelope (Env) trimer, the sole viral antigen on the virion surface. Antibodies isolated from HIV-1-infected donors, however, have been shown to recognize all major exposed regions of the prefusion-closed Env trimer, and an emerging understanding of the immunological and structural characteristics of these antibodies and the epitopes they recognize is enabling new approaches to vaccine design. Antibody lineage-based design creates immunogens that activate the naive ancestor-B cell of a target antibody lineage and that mature intermediate-B cells toward effective neutralization, with proof of principle achieved with select HIV-1-neutralizing antibody lineages in human-gene knock-in mouse models. Epitope-based vaccine design involves the engineering of sites of Env vulnerability as defined by the recognition of broadly neutralizing antibodies, with cross-reactive neutralizing antibodies elicited in animal models. Both epitope-based and antibody lineage-based HIV-1 vaccine approaches are being readied for human clinical trials.

Teaser

Kwong and Mascola review vaccine approaches to overcome the formidable challenge of eliciting effective antibodies against HIV-1. The structural and immunological information provided by analysis of infection-elicited broadly neutralizing antibodies provides a framework for antibody-to-vaccine approaches of vaccine design.

Targeting the Latent Reservoir for HIV-1

15 May 2018

Publication date: 15 May 2018
Source:Immunity, Volume 48, Issue 5

Author(s): Srona Sengupta, Robert F. Siliciano

Antiretroviral therapy can effectively block HIV-1 replication and prevent or reverse immunodeficiency in HIV-1-infected individuals. However, viral replication resumes within weeks of treatment interruption. The major barrier to a cure is a small pool of resting memory CD4⁺ T cells that harbor latent HIV-1 proviruses. This latent reservoir is now the focus of an intense international research effort. We describe how the reservoir is established, challenges involved in eliminating it, and pharmacologic and immunologic strategies for targeting this reservoir. The development of a successful cure strategy will most likely require understanding the mechanisms that maintain HIV-1 proviruses in a latent state and pathways that drive the proliferation of infected cells, which slows reservoir decay. In addition, a cure will require the development of effective immunologic approaches to eliminating infected cells. There is renewed optimism about the prospect of a cure, and the interventions discussed here could pave the way.

Teaser

Developing a cure for HIV-1 requires understanding the mechanisms of HIV-1 persistence in the latent reservoir. In this review, we discuss historical and recent paradigms in the HIV-1 persistence field as well as novel immunologic and pharmacologic strategies for eliminating this reservoir.

Niches for Hematopoietic Stem Cells and Their Progeny

17 April 2018

Publication date: 17 April 2018
Source:Immunity, Volume 48, Issue 4

Author(s): Qiaozhi Wei, Paul S. Frenette

Steady-state hematopoietic stem cells’ (HSCs) self-renewal and differentiation toward their mature progeny in the adult bone marrow is tightly regulated by cues from the microenvironment. Recent insights into the cellular and molecular constituents have uncovered a high level of complexity. Here, we review emerging evidence showing how HSCs and their progeny are regulated by an interdependent network of mesenchymal stromal cells, nerve fibers, the vasculature, and also other hematopoietic cells. Understanding the interaction mechanisms in these intricate niches will provide great opportunities for HSC-related therapies and immune modulation.

Teaser

The adult bone marrow provides essential niches for hematopoietic stem cell (HSC) maintenance and differentiation, which are not fully understood. Here we review the currently known cellular and molecular components of the niche for hematopoietic stem cells and their progeny, highlight their heterogeneity and interdependency, and discuss some open questions in the field.

Cancer-Cell-Intrinsic Mechanisms Shaping the Tumor Immune Landscape

20 March 2018

Publication date: 20 March 2018
Source:Immunity, Volume 48, Issue 3

Author(s): Max D. Wellenstein, Karin E. de Visser

Owing to their tremendous diversity and plasticity, immune cells exert multifaceted functions in tumor-bearing hosts, ranging from anti-tumor to pro-tumor activities. Tumor immune landscapes differ greatly between and within cancer types. Emerging evidence suggests that genetic aberrations in cancer cells dictate the immune contexture of tumors. Here, we review the current understanding of the mechanisms whereby common drivers of tumorigenesis modulate the tumor immune milieu. We discuss these findings in the context of clinical observations and examine how cancer-cell-intrinsic properties can be exploited to maximize the benefit of immunomodulatory therapies. Understanding the relationship between cancer cell-intrinsic genetic events and the immune response may enable personalized immune intervention strategies for cancer patients.

Teaser

Wellenstein and de Visser review the mechanisms whereby drivers of tumorigenesis shape the tumor microenvironment and tumor immunity and place these findings in the context of clinical observations of responsiveness and resistance to immune checkpoint blockade therapies.

Combination Cancer Therapy with Immune Checkpoint Blockade: Mechanisms and Strategies

20 March 2018

Publication date: 20 March 2018
Source:Immunity, Volume 48, Issue 3

Author(s): Shetal A. Patel, Andy J. Minn

The success of immune checkpoint blockade in patients with a wide variety of malignancies has changed the treatment paradigm in oncology. However, combination therapies with immune checkpoint blockade will be needed to overcome resistance and broaden the clinical utility of immunotherapy. Here we discuss a framework for rationally designing combination therapy strategies based on enhancing major discriminatory functions of the immune system that are corrupted by cancer—namely, antigenicity, adjuvanticity, and homeostatic feedback inhibition. We review recent advances on how conventional genotoxic cancer therapies, molecularly targeted therapies, epigenetic agents, and immune checkpoint inhibitors can restore these discriminatory functions. Potential barriers that can impede response despite combination therapy are also discussed.

Teaser

Patel and Minn present a conceptual framework for the design of combination therapies wherein combination approaches are aimed at restoring discriminatory functions of the immune system that are corrupted by cancer—antigenicity, adjuvanticity, and feedback inhibition.

Regulation and Function of the PD-L1 Checkpoint

20 March 2018

Publication date: 20 March 2018
Source:Immunity, Volume 48, Issue 3

Author(s): Chong Sun, Riccardo Mezzadra, Ton N. Schumacher

Expression of programmed death-ligand 1 (PD-L1) is frequently observed in human cancers. Binding of PD-L1 to its receptor PD-1 on activated T cells inhibits anti-tumor immunity by counteracting T cell-activating signals. Antibody-based PD-1-PD-L1 inhibitors can induce durable tumor remissions in patients with diverse advanced cancers, and thus expression of PD-L1 on tumor cells and other cells in the tumor microenviroment is of major clinical relevance. Here we review the roles of the PD-1-PD-L1 axis in cancer, focusing on recent findings on the mechanisms that regulate PD-L1 expression at the transcriptional, posttranscriptional, and protein level. We place this knowledge in the context of observations in the clinic and discuss how it may inform the design of more precise and effective cancer immune checkpoint therapies.

Teaser

Schumacher et al. review the mechanisms that control PD-L1 expression in cancer and discuss how the growing understanding of the regulation and function of the PD-1-PD-L1 axis can guide more precise and effective immune checkpoint therapies.

Unconventional T Cell Targets for Cancer Immunotherapy

20 March 2018

Publication date: 20 March 2018
Source:Immunity, Volume 48, Issue 3

Author(s): Dale I. Godfrey, Jérôme Le Nours, Daniel M. Andrews, Adam P. Uldrich, Jamie Rossjohn

Most studies on the immunotherapeutic potential of T cells have focused on CD8 and CD4 T cells that recognize peptide antigens (Ag) presented by polymorphic major histocompatibility complex (MHC) class I and MHC class II molecules, respectively. However, unconventional T cells, which interact with MHC class Ib and MHC-I like molecules, are also implicated in tumor immunity, although their role therein is unclear. These include unconventional T cells targeting MHC class Ib molecules such as HLA-E and its murine ortholog Qa-1b, natural killer T (NKT) cells, mucosal associated invariant T (MAIT) cells, and γδ T cells. Here, we review the current understanding of the roles of these unconventional T cells in tumor immunity and discuss why further studies into the immunotherapeutic potential of these cells is warranted.

Teaser

Godfrey et al. review the current understanding of the roles of unconventional T cells in tumor immunity, and discuss the therapeutic potential of harnessing the anti-tumor functions of cells characterized by repeated patterns of TCR usage in unrelated individuals.

Human T Cell Development, Localization, and Function throughout Life

20 February 2018

Publication date: 20 February 2018
Source:Immunity, Volume 48, Issue 2

Author(s): Brahma V. Kumar, Thomas J. Connors, Donna L. Farber

Throughout life, T cells coordinate multiple aspects of adaptive immunity, including responses to pathogens, allergens, and tumors. In mouse models, the role of T cells is studied in the context of a specific type of pathogen, antigen, or disease condition over a limited time frame, whereas in humans, T cells control multiple insults simultaneously throughout the body and maintain immune homeostasis over decades. In this review, we discuss how human T cells develop and provide essential immune protection at different life stages and highlight tissue localization and subset delineation as key determinants of the T cell functional role in immune responses. We also discuss how anatomic compartments undergo distinct age-associated changes in T cell subset composition and function over a lifetime. It is important to consider age and tissue influences on human T cells when developing targeted strategies to modulate T cell-mediated immunity in vaccines and immunotherapies.

Teaser

Recent studies of human T cells in diverse tissue sites have revealed that the functional role of T cells is closely linked to the anatomical location, subset, and developmental stage. Kumar et al. review these advances and highlight human-specific aspects of T cell immunity.

Understanding Subset Diversity in T Cell Memory

20 February 2018

Publication date: 20 February 2018
Source:Immunity, Volume 48, Issue 2

Author(s): Stephen C. Jameson, David Masopust

Considerable advances have been made in recent years in understanding the generation and function of memory T cells. Memory T cells are typically parsed into discreet subsets based on phenotypic definitions that connote distinct roles in immunity. Here we consider new developments in the field and focus on how emerging differences between memory cells with respect to their trafficking, metabolism, epigenetic regulation, and longevity may fail to fit into small groups of “memory subsets.” Rather, the properties of individual memory T cells fall on a continuum within each of these and other parameters. We discuss how this continuum influences the way that the efficacy of vaccination is assessed, as well as the suitability of a memory population for protective immunity.

Teaser

Memory T cells are typically parsed into discreet subsets based on phenotypic definitions that connote distinct roles in immunity. Jameson and Masopust argue that the conventional subset nomenclature fails to accurately encompass the distribution of functional traits within this diverse population.

Regulation of the Immune Response by the Aryl Hydrocarbon Receptor

16 January 2018

Publication date: 16 January 2018
Source:Immunity, Volume 48, Issue 1

Author(s): Cristina Gutiérrez-Vázquez, Francisco J. Quintana

The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that is activated by small molecules provided by the diet, microorganisms, metabolism, and pollutants. AhR is expressed by a number of immune cells, and thus AhR signaling provides a molecular pathway that integrates the effects of the environment and metabolism on the immune response. Studies have shown that AhR signaling plays important roles in the immune system in health and disease. As its activity is regulated by small molecules, AhR also constitutes a potential target for therapeutic immunomodulation. In this review we discuss the role of AhR in the regulation of the immune response in the context of autoimmunity, infection, and cancer, as well as the potential opportunities and challenges of developing AhR-targeted therapeutics.

Teaser

AhR signaling integrates the effects of the environment and metabolism on the immune response. Gutiérrez-Vázquez and Quintana review the role of AhR in the regulation of the immune response in the context of autoimmunity, infection, and cancer, and discuss the potential opportunities and challenges of developing AhR-targeted therapeutics.

Recent Advances in Type-2-Cell-Mediated Immunity: Insights from Helminth Infection

19 December 2017

Publication date: 19 December 2017
Source:Immunity, Volume 47, Issue 6

Author(s): Nicola L. Harris, P’ng Loke

Type-2-cell-mediated immune responses play a critical role in mediating both host-resistance and disease-tolerance mechanisms during helminth infections. Recently, type 2 cell responses have emerged as major regulators of tissue repair and metabolic homeostasis even under steady-state conditions. In this review, we consider how studies of helminth infection have contributed toward our expanding cellular and molecular understanding of type-2-cell-mediated immunity, as well as new areas such as the microbiome. By studying how these successful parasites form chronic infections without overt pathology, we are gaining additional insights into allergic and inflammatory diseases, as well as normal physiology.

Teaser

Type-2-cell-mediated immune responses play critical roles in regulating host resistance against helminths and promoting tissue repair and metabolic homeostasis. Harris and Loke review recent advances in the field resulting from studies of helminth-host interactions and provide insight into the activation and function of type 2 immune cells.

The Broad Spectrum of Human Natural Killer Cell Diversity

21 November 2017

Publication date: 21 November 2017
Source:Immunity, Volume 47, Issue 5

Author(s): Aharon G. Freud, Bethany L. Mundy-Bosse, Jianhua Yu, Michael A. Caligiuri

Natural killer (NK) cells provide protection against infectious pathogens and cancer. For decades it has been appreciated that two major NK cell subsets (CD56^bright and CD56^dim) exist in humans and have distinct anatomical localization patterns, phenotypes, and functions in immunity. In light of this traditional NK cell dichotomy, it is now clear that the spectrum of human NK cell diversity is much broader than originally appreciated as a result of variegated surface receptor, intracellular signaling molecule, and transcription factor expression; tissue-specific imprinting; and foreign antigen exposure. The recent discoveries of tissue-resident NK cell developmental intermediates, non-NK innate lymphoid cells, and the capacity for NK cells to adapt and differentiate into long-lived memory cells has added further complexity to this field. Here we review our current understanding of the breadth and generation of human NK cell diversity.

Teaser

Recent advances in the field of human natural killer cell biology have revealed that there is a remarkably high amount of cellular diversity within different tissues. Freud et al. review these advances and provide insight into the generation of natural killer cell diversity and its roles in innate immunity.

Monocyte-Macrophages and T Cells in Atherosclerosis

17 October 2017

Publication date: 17 October 2017
Source:Immunity, Volume 47, Issue 4

Author(s): Ira Tabas, Andrew H. Lichtman

Atherosclerosis is an arterial disease process characterized by the focal subendothelial accumulation of apolipoprotein-B-containing lipoproteins, immune and vascular wall cells, and extracellular matrix. The lipoproteins acquire features of damage-associated molecular patterns and trigger first an innate immune response, dominated by monocyte-macrophages, and then an adaptive immune response. These inflammatory responses often become chronic and non-resolving and can lead to arterial damage and thrombosis-induced organ infarction. The innate immune response is regulated at various stages, from hematopoiesis to monocyte changes and macrophage activation. The adaptive immune response is regulated primarily by mechanisms that affect the balance between regulatory and effector T cells. Mechanisms related to cellular cholesterol, phenotypic plasticity, metabolism, and aging play key roles in affecting these responses. Herein, we review select topics that shed light on these processes and suggest new treatment strategies.

Teaser

Atherosclerosis is an arterial disease process characterized by the focal subendothelial accumulation of apolipoprotein-B-containing lipoproteins, immune and vascular wall cells, and extracellular matrix. The lipoproteins acquire features of damage-associated molecular patterns and trigger first an innate immune response, dominated by monocyte-macrophages, and then an adaptive immune response. These inflammatory responses often become chronic and non-resolving and can lead to arterial damage and thrombosis-induced organ infarction. The innate immune response is regulated at various stages, from hematopoiesis to monocyte changes and macrophage activation. The adaptive immune response is regulated primarily by mechanisms that affect the balance between regulatory and effector T cells. Mechanisms related to cellular cholesterol, phenotypic plasticity, metabolism, and aging play key roles in regulating these responses. Herein, we review select topics that shed light on these processes and suggest new treatment strategies.

Foundations of Immunometabolism and Implications for Metabolic Health and Disease

19 September 2017

Publication date: 19 September 2017
Source:Immunity, Volume 47, Issue 3

Author(s): Gökhan S. Hotamisligil

Highly ordered interactions between immune and metabolic responses are evolutionarily conserved and paramount for tissue and organismal health. Disruption of these interactions underlies the emergence of many pathologies, particularly chronic non-communicable diseases such as obesity and diabetes. Here, we examine decades of research identifying the complex immunometabolic signaling networks and the cellular and molecular events that occur in the setting of altered nutrient and energy exposures and offer a historical perspective. Furthermore, we describe recent advances such as the discovery that a broad complement of immune cells play a role in immunometabolism and the emerging evidence that nutrients and metabolites modulate inflammatory pathways. Lastly, we discuss how this work may eventually lead to tangible therapeutic advancements to promote health.

Teaser

It is now well established that the immune and metabolic systems physically and functionally interact to maintain homeostasis, and abnormalities in these interactions are critical contributors to metabolic diseases. This review from Gökhan Hotamisligil summarizes the foundation and growth of the dynamic field of immunometabolism.

Fcγ Receptor Function and the Design of Vaccination Strategies

15 August 2017

Publication date: 15 August 2017
Source:Immunity, Volume 47, Issue 2

Author(s): Stylianos Bournazos, Jeffrey V. Ravetch

Through specific interactions with distinct types of Fcγ receptors (FcγRs), the Fc domain of immunoglobulin G (IgG) mediates a wide spectrum of immunological functions that influence both innate and adaptive responses. Recent studies indicate that IgG Fc-FcγR interactions are dynamically regulated during an immune response through the control of the Fc-associated glycan structure and Ig subclass composition on the one hand and selective FcγR expression on immune cells on the other, which together determine the capacity of IgG to interact in a cell-type-specific manner with specific members of the FcγR family. Here, we present a framework that synthesizes the current understanding of the contribution of FcγR pathways to the induction and regulation of antibody and T cell responses. Within this context, we discuss vaccination strategies to elicit broad and potent immune responses based on the immunomodulatory properties of Fc-FcγR interactions.

Teaser

Through specific interactions with distinct types of Fcγ receptors (FcγRs), the Fc domain of immunoglobulin G (IgG) mediates a wide spectrum of immunological functions that influence both innate and adaptive responses. Recent studies indicate that IgG-Fc-FcγR interactions are dynamically regulated during an immune response through the control of the Fc-associated glycan structure and Ig subclass composition on the one hand and selective FcγR expression on immune cells on the other, which together determine the capacity of IgG to interact in a cell-type-specific manner with specific members of the FcγR family. Here, we present a framework that synthesizes the current understanding of the contribution of FcγR pathways to the induction and regulation of antibody and T cell responses. Within this context, we discuss vaccination strategies to elicit broad and potent immune responses based on the immunomodulatory properties of Fc-FcγR interactions.

The P2X7 Receptor in Infection and Inflammation

18 July 2017

Publication date: 18 July 2017
Source:Immunity, Volume 47, Issue 1

Author(s): Francesco Di Virgilio, Diego Dal Ben, Alba Clara Sarti, Anna Lisa Giuliani, Simonetta Falzoni

Adenosine triphosphate (ATP) accumulates at sites of tissue injury and inflammation. Effects of extracellular ATP are mediated by plasma membrane receptors named P2 receptors (P2Rs). The P2R most involved in inflammation and immunity is the P2X7 receptor (P2X7R), expressed by virtually all cells of innate and adaptive immunity. P2X7R mediates NLRP3 inflammasome activation, cytokine and chemokine release, T lymphocyte survival and differentiation, transcription factor activation, and cell death. Ten human P2RX7 gene splice variants and several SNPs that produce complex haplotypes are known. The P2X7R is a potent stimulant of inflammation and immunity and a promoter of cancer cell growth. This makes P2X7R an appealing target for anti-inflammatory and anti-cancer therapy. However, an in-depth knowledge of its structure and of the associated signal transduction mechanisms is needed for an effective therapeutic development.

Teaser

Extracellular ATP is a common constitutent of the inflammatory milieu, where it modulates immune cell responses by activating a family of plasma membrane receptors named P2. In this review, Di Virgilio et al. discuss the central role played by the P2X7 receptor in promoting inflammation and driving innate and adaptive immunity.

Immunology of Food Allergy

18 July 2017

Publication date: 18 July 2017
Source:Immunity, Volume 47, Issue 1

Author(s): Leticia Tordesillas, M. Cecilia Berin, Hugh A. Sampson

Many consider food allergy as the “second wave” of the allergy epidemic following the “first wave” of respiratory allergy, i.e., asthma and allergic rhinitis, plaguing westernized countries, with up to 8% of young children and 2%–3% of adults in the United States now affected by hypersensitivity reactions to various foods. In the past decade, there have been great strides in our understanding of the underlying immunopathogenesis of these disorders, which have led to improved diagnostic techniques, management strategies, and therapeutic approaches. Here we will review the most recent understanding of basic mechanisms underlying IgE-mediated food allergies and novel therapeutic approaches under investigation for both the prevention and treatment of IgE-mediated food allergies.

Teaser

Food allergies have increased exponentially in the last decades. Tordesillas et al. review the immune mechanisms of sensitization to foods and recent developments in the prevention of food allergies. In addidtion, they discuss efficacy of antigen-specific immunotherapies as well as other emerging therapeutic approaches.

Protective and Pathological Immunity during Central Nervous System Infections

20 June 2017

Publication date: 20 June 2017
Source:Immunity, Volume 46, Issue 6

Author(s): Robyn S. Klein, Christopher A. Hunter

The concept of immune privilege of the central nervous system (CNS) has dominated the study of inflammatory processes in the brain. However, clinically relevant models have highlighted that innate pathways limit pathogen invasion of the CNS and adaptive immunity mediates control of many neural infections. As protective responses can result in bystander damage, there are regulatory mechanisms that balance protective and pathological inflammation, but these mechanisms might also allow microbial persistence. The focus of this review is to consider the host-pathogen interactions that influence neurotropic infections and to highlight advances in our understanding of innate and adaptive mechanisms of resistance as key determinants of the outcome of CNS infection. Advances in these areas have broadened our comprehension of how the immune system functions in the brain and can readily overcome immune privilege.

Teaser

The CNS utilizes multiple mechanisms to restrict microbial entry but there are also innate and adaptive mechanisms that control pathogens that access this immune privileged site. Klein and Hunter review the pathogen interactions with the blood brain barrier and resident glial populations that govern the outcome of CNS infection, as well as the immune mechanisms that dictate protective and pathological responses in the brain.

The Enteric Network: Interactions between the Immune and Nervous Systems of the Gut

20 June 2017

Publication date: 20 June 2017
Source:Immunity, Volume 46, Issue 6

Author(s): Bryan B. Yoo, Sarkis K. Mazmanian

Interactions between the nervous and immune systems enable the gut to respond to the variety of dietary products that it absorbs, the broad spectrum of pathogens that it encounters, and the diverse microbiome that it harbors. The enteric nervous system (ENS) senses and reacts to the dynamic ecosystem of the gastrointestinal (GI) tract by translating chemical cues from the environment into neuronal impulses that propagate throughout the gut and into other organs in the body, including the central nervous system (CNS). This review will describe the current understanding of the anatomy and physiology of the GI tract by focusing on the ENS and the mucosal immune system. We highlight emerging literature that the ENS is essential for important aspects of microbe-induced immune responses in the gut. Although most basic and applied research in neuroscience has focused on the brain, the proximity of the ENS to the immune system and its interface with the external environment suggest that novel paradigms for nervous system function await discovery.

Teaser

After its initial discoveries in the 1980s and 1990s, neuro-immunology is experiencing a rebirth in the scientific literature. As knowledge of the gastrointestinal tract expands, including its neuronal, immunological, and microbial constituents, in this review, Yoo and Mazmanian provide new perspectives and hypotheses regarding mucosal neuro-immunology.

Mechanisms and Therapeutic Relevance of Neuro-immune Communication

20 June 2017

Publication date: 20 June 2017
Source:Immunity, Volume 46, Issue 6

Author(s): Sangeeta S. Chavan, Valentin A. Pavlov, Kevin J. Tracey

Active research at the frontiers of immunology and neuroscience has identified multiple points of interaction and communication between the immune system and the nervous system. Immune cell activation stimulates neuronal circuits that regulate innate and adaptive immunity. Molecular mechanistic insights into the inflammatory reflex and other neuro-immune interactions have greatly advanced our understanding of immunity and identified new therapeutic possibilities in inflammatory and autoimmune diseases. Recent successful clinical trials using bioelectronic devices that modulate the inflammatory reflex to significantly ameliorate rheumatoid arthritis and inflammatory bowel disease provide a path for using electrons as a therapeutic modality for targeting molecular mechanisms of immunity. Here, we review mechanisms of peripheral sensory neuronal function in response to immune challenges, the neural regulation of immunity and inflammation, and the therapeutic implications of those mechanistic insights.

Teaser

In this review Chavan, Pavlov, and Tracey discuss mechanisms at the interface of the immune system and the nervous system as well as the role of neural pathways in the regulation of immunity. They also summarize the therapeutic implications of neuromodulation in animal models and clinical settings of inflammatory and autoimmune disease.

Myeloid Cells in the Central Nervous System

20 June 2017

Publication date: 20 June 2017
Source:Immunity, Volume 46, Issue 6

Author(s): Jasmin Herz, Anthony J. Filiano, Ashtyn Smith, Nir Yogev, Jonathan Kipnis

The central nervous system (CNS) and its meningeal coverings accommodate a diverse myeloid compartment that includes parenchymal microglia and perivascular macrophages, as well as choroid plexus and meningeal macrophages, dendritic cells, and granulocytes. These myeloid populations enjoy an intimate relationship with the CNS, where they play an essential role in both health and disease. Although the importance of these cells is clearly recognized, their exact function in the CNS continues to be explored. Here, we review the subsets of myeloid cells that inhabit the parenchyma, meninges, and choroid plexus and discuss their roles in CNS homeostasis. We also discuss the role of these cells in various neurological pathologies, such as autoimmunity, mechanical injury, neurodegeneration, and infection. We highlight the neuroprotective nature of certain myeloid cells by emphasizing their therapeutic potential for the treatment of neurological conditions.

Teaser

In this review, Herz et al. discuss the vital roles of myeloid cells in central nervous system (CNS) homeostasis and their dysregulation in neurological disorders. The review covers the participation of myeloid cells in pathophysiological processes such as autoimmunity, degeneration, injury, and infection.

Reactive Astrocytes: Production, Function, and Therapeutic Potential

20 June 2017

Publication date: 20 June 2017
Source:Immunity, Volume 46, Issue 6

Author(s): Shane A. Liddelow, Ben A. Barres

Astrocytes constitute approximately 30% of the cells in the mammalian central nervous system (CNS). They are integral to brain and spinal-cord physiology and perform many functions important for normal neuronal development, synapse formation, and proper propagation of action potentials. We still know very little, however, about how these functions change in response to immune attack, chronic neurodegenerative disease, or acute trauma. In this review, we summarize recent studies that demonstrate that different initiating CNS injuries can elicit at least two types of “reactive” astrocytes with strikingly different properties, one type being helpful and the other harmful. We will also discuss new methods for purifying and investigating reactive-astrocyte functions and provide an overview of new markers for delineating these different states of reactive astrocytes. The discovery that astrocytes have different types of reactive states has important implications for the development of new therapies for CNS injury and diseases.

Teaser

Liddelow and Barres review recent work indicating that in response to injury and disease, immune cells release cytokines that activate astrocytes to one of at least two reactive states: one helpful and one harmful. They discuss new methods for purifying and investigating reactive astrocyte functions and provide an overview of new markers for delineating reactive-astrocyte states.

Biochemical Underpinnings of Immune Cell Metabolic Phenotypes

16 May 2017

Publication date: 16 May 2017
Source:Immunity, Volume 46, Issue 5

Author(s): Benjamin A. Olenchock, Jeffrey C. Rathmell, Matthew G. Vander Heiden

The metabolism of immune cells affects their function and influences host immunity. This review explores how immune cell metabolic phenotypes reflect biochemical dependencies and highlights evidence that both the metabolic state of immune cells and nutrient availability can alter immune responses. The central importance of oxygen, energetics, and redox homeostasis in immune cell metabolism, and how these factors are reflected in different metabolic phenotypes, is also discussed. Linking immune cell metabolic phenotype to effector functions is important to understand how altering metabolism can impact the way in which immune cells meet their metabolic demands and affect the immune response in various disease contexts.

Teaser

The metabolic phenotype of immune cells reflects the biochemical adaptations these cells use to support function. This review summarizes how metabolism is adapted to meet the energetic and redox demands of immune cell populations.

Metabolic and Epigenetic Coordination of T Cell and Macrophage Immunity

16 May 2017

Publication date: 16 May 2017
Source:Immunity, Volume 46, Issue 5

Author(s): Anthony T. Phan, Ananda W. Goldrath, Christopher K. Glass

Recognition of pathogens by innate and adaptive immune cells instructs rapid alterations of cellular processes to promote effective resolution of infection. To accommodate increased bioenergetic and biosynthetic demands, metabolic pathways are harnessed to maximize proliferation and effector molecule production. In parallel, activation initiates context-specific gene-expression programs that drive effector functions and cell fates that correlate with changes in epigenetic landscapes. Many chromatin- and DNA-modifying enzymes make use of substrates and cofactors that are intermediates of metabolic pathways, providing potential cross talk between metabolism and epigenetic regulation of gene expression. In this review, we discuss recent studies of T cells and macrophages supporting a role for metabolic activity in integrating environmental signals with activation-induced gene-expression programs through modulation of the epigenome and speculate as to how this may influence context-specific macrophage and T cell responses to infection.

Teaser

Pathogen detection induces gene expression and metabolic shifts in immune cells to facilitate effector programs. Phan, Goldrath, and Glass review emerging evidence that metabolic activity modulates “writers” and “erasers” of the epigenetic landscape and discuss how this may tailor tissue-specific activity of macrophages and T cells.

MenTORing Immunity: mTOR Signaling in the Development and Function of Tissue-Resident Immune Cells

16 May 2017

Publication date: 16 May 2017
Source:Immunity, Volume 46, Issue 5

Author(s): Russell G. Jones, Edward J. Pearce

Tissue-resident immune cells must balance survival in peripheral tissues with the capacity to respond rapidly upon infection or tissue damage, and in turn couple these responses with intrinsic metabolic control and conditions in the tissue microenvironment. The serine/threonine kinase mammalian/mechanistic target of rapamycin (mTOR) is a central integrator of extracellular and intracellular growth signals and cellular metabolism and plays important roles in both innate and adaptive immune responses. This review discusses the function of mTOR signaling in the differentiation and function of tissue-resident immune cells, with focus on the role of mTOR as a metabolic sensor and its impact on metabolic regulation in innate and adaptive immune cells. We also discuss the impact of metabolic constraints in tissues on immune homeostasis and disease, and how manipulating mTOR activity with drugs such as rapamycin can modulate immunity in these contexts.

Teaser

Mechanistic Target of Rapamycin is a molecular checkpoint that regulates cellular anabolism to match nutrient availability and bioenergetic requirements. Jones and Pearce review the role of mTOR in tissue-resident immune cells, which rapidly shift between resting and activated states in response to extracellular signals linked to infection and danger.

Metabolic Regulation of the Immune Humoral Response

16 May 2017

Publication date: 16 May 2017
Source:Immunity, Volume 46, Issue 5

Author(s): Mark Boothby, Robert C. Rickert

Productive humoral responses require that naive B cells and their differentiated progeny move among distinct micro-environments. In this review, we discuss how studies are beginning to address the nature of these niches as well as the interplay between cellular signaling, metabolic programming, and adaptation to the locale. Recent work adds evidence to the expectation that B cells at distinct stages of development or functional subsets are influenced by the altered profiles of nutrients and metabolic by-products that distinguish these sites. Moreover, emerging findings reveal a cross-talk among the external milieu, signal transduction pathways, and transcription factors that direct B cell fate in the periphery.

Teaser

The metabolic needs of cells of the B lineage differ dramatically, spanning the quiescent naive and memory states, antigen-driven germinal center B cell stages, and terminal differentiation state as antibody-producing cells. Boothby and Rickert outline the metabolic inputs and corresponding pathways that impact peripheral B cell differentiation in distinct microenvironments.

Regionalized Development and Maintenance of the Intestinal Adaptive Immune Landscape

18 April 2017

Publication date: 18 April 2017
Source:Immunity, Volume 46, Issue 4

Author(s): William W. Agace, Kathy D. McCoy

The intestinal immune system has the daunting task of protecting us from pathogenic insults while limiting inflammatory responses against the resident commensal microbiota and providing tolerance to food antigens. This role is particularly impressive when one considers the vast mucosal surface and changing landscape that the intestinal immune system must monitor. In this review, we highlight regional differences in the development and composition of the adaptive immune landscape of the intestine and the impact of local intrinsic and environmental factors that shape this process. To conclude, we review the evidence for a critical window of opportunity for early-life exposures that affect immune development and alter disease susceptibility later in life.

Teaser

Agace and McCoy discuss regional differences in the development and composition of the adaptive immune landscape of the intestine and the impact of local intrinsic and environmental factors that shape this process, including evidence for a critical window of opportunity for early-life exposures that affect immune development and alter disease susceptibility later in life.

Lung Homeostasis: Influence of Age, Microbes, and the Immune System

18 April 2017

Publication date: 18 April 2017
Source:Immunity, Volume 46, Issue 4

Author(s): Clare M. Lloyd, Benjamin J. Marsland

Pulmonary immune homeostasis is maintained by a network of tissue-resident cells that continually monitor the external environment, and in health, instruct tolerance to innocuous inhaled particles while ensuring that efficient and rapid immune responses can be mounted against invading pathogens. Here we review the multiple pathways that underlie effective lung immunity in health, and discuss how these may be affected by external environmental factors and contribute to chronic inflammation during disease. In this context, we examine the current understanding of the impact of the microbiota in immune development and function and in the setting of the threshold for immune responses that maintains the balance between tolerance and chronic inflammation in the lung. We propose that host interactions with microbes are critical for establishing the immune landscape of the lungs.

Teaser

Lloyd and Marsland review the multiple pathways that underlie effective lung immunity in health and discuss the impact of the microbiota in lung immune development and function, including the setting of the threshold for immune responses that maintains the balance between tolerance and chronic inflammation in the lung.

Homeostatic Immunity and the Microbiota

18 April 2017

Publication date: 18 April 2017
Source:Immunity, Volume 46, Issue 4

Author(s): Yasmine Belkaid, Oliver J. Harrison

The microbiota plays a fundamental role in the induction, education, and function of the host immune system. In return, the host immune system has evolved multiple means by which to maintain its symbiotic relationship with the microbiota. The maintenance of this dialogue allows the induction of protective responses to pathogens and the utilization of regulatory pathways involved in the sustained tolerance to innocuous antigens. The ability of microbes to set the immunological tone of tissues, both locally and systemically, requires tonic sensing of microbes and complex feedback loops between innate and adaptive components of the immune system. Here we review the dominant cellular mediators of these interactions and discuss emerging themes associated with our current understanding of the homeostatic immunological dialogue between the host and its microbiota.

Teaser

The microbiota plays a fundamental role in the induction, education, and function of the host immune system, and in turn, the host immune system maintains this symbiotic relationship via diverse mechanisms. Belkaid and Harrison (2017) review the dominant cellular mediators of these interactions and discuss emerging themes in the homeostatic immunological dialogue between the host and its microbiota.

Protecting the Newborn and Young Infant from Infectious Diseases: Lessons from Immune Ontogeny

21 March 2017

Publication date: 21 March 2017
Source:Immunity, Volume 46, Issue 3

Author(s): Tobias R. Kollmann, Beate Kampmann, Sarkis K. Mazmanian, Arnaud Marchant, Ofer Levy

Infections in the first year of life are common and often severe. The newborn host demonstrates both quantitative and qualitative differences to the adult in nearly all aspects of immunity, which at least partially explain the increased susceptibility to infection. Here we discuss how differences in susceptibility to infection result not out of a state of immaturity, but rather reflect adaptation to the particular demands placed on the immune system in early life. We review the mechanisms underlying host defense in the very young, and discuss how specific developmental demands increase the risk of particular infectious diseases. In this context, we discuss how this plasticity, i.e. the capacity to adapt to demands encountered in early life, also provides the potential to leverage protection of the young against infection and disease through a number of interventions.

Teaser

Infections in the first year of life are common and often severe. The newborn host demonstrates both quantitative and qualitative differences to the adult in nearly all aspects of immunity, which at least partially explain the increased susceptibility to infection. Here we discuss how differences in susceptibility to infection result not out of a state of immaturity, but rather reflect adaptation to the particular demands placed on the immune system in early life. We review the mechanisms underlying host defense in the very young, and discuss how specific developmental demands increase the risk of particular infectious diseases. In this context, we discuss how this plasticity, i.e. the capacity to adapt to demands observed in early life, also provides the potential to leverage protection of the young against infection and disease through a number of interventions.

Successful and Maladaptive T Cell Aging

21 March 2017

Publication date: 21 March 2017
Source:Immunity, Volume 46, Issue 3

Author(s): Jörg J. Goronzy, Cornelia M. Weyand

Throughout life, the T cell system adapts to shifting resources and demands, resulting in a fundamentally restructured immune system in older individuals. Here we review the cellular and molecular features of an aged immune system and discuss the trade-offs inherent to these adaptive mechanisms. Processes include homeostatic proliferation that maintains compartment size at the expense of partial loss in stemness and incomplete differentiation and the activation of negative regulatory programs, which constrain effector T cell expansion and prevent increasing oligoclonality but also interfere with memory cell generation. We propose that immune failure occurs when adaptive strategies developed by the aging T cell system fail and also discuss how, in some settings, the programs associated with T cell aging culminates in a maladaptive response that directly contributes to chronic inflammatory disease.

Teaser

Throughout life, the T cell system adapts to shifting resources and demands, resulting in a fundamentally restructured immune system in older individuals. Goronzy and Weyand review the cellular and molecular features of an aged immune system and discuss the trade-offs inherent to these adaptive mechanisms and their impact in health and disease.

Immunopathogenesis of Rheumatoid Arthritis

21 February 2017

Publication date: 21 February 2017
Source:Immunity, Volume 46, Issue 2

Author(s): Gary S. Firestein, Iain B. McInnes

Rheumatoid arthritis (RA) is the most common inflammatory arthropathy. The majority of evidence, derived from genetics, tissue analyses, models, and clinical studies, points to an immune-mediated etiology associated with stromal tissue dysregulation that together propogate chronic inflammation and articular destruction. A pre-RA phase lasting months to years may be characterized by the presence of circulating autoantibodies, increasing concentration and range of inflammatory cytokines and chemokines, and altered metabolism. Clinical disease onset comprises synovitis and systemic comorbidities affecting the vasculature, metabolism, and bone. Targeted immune therapeutics and aggressive treatment strategies have substantially improved clinical outcomes and informed pathogenetic understanding, but no cure as yet exists. Herein we review recent data that support intriguing models of disease pathogenesis. They allude to the possibility of restoration of immunologic homeostasis and thus a state of tolerance associated with drug-free remission. This target represents a bold vision for the future of RA therapeutics.

Teaser

Elucidation of the immune pathogenesis of rheumatoid arthritis has prompted significant therapeutic progress. Firestein and McInnes review recent advances in understanding of immune dysregulation and stromal pathology in RA that promote development and perpetuation of disease and offer exciting new therapeutic potential.

Neutrophils in Homeostasis, Immunity, and Cancer

17 January 2017

Publication date: 17 January 2017
Source:Immunity, Volume 46, Issue 1

Author(s): José Ángel Nicolás-Ávila, José M. Adrover, Andrés Hidalgo

Neutrophils were among the first leukocytes described and visualized by early immunologists. Prominent effector functions during infection and sterile inflammation classically placed them low in the immune tree as rapid, mindless aggressors with poor regulatory functions. This view is currently under reassessment as we uncover new aspects of their life cycle and identify transcriptional and phenotypic diversity that endows them with regulatory properties that extend beyond their lifetime in the circulation. These properties are revealing unanticipated roles for neutrophils in supporting homeostasis, as well as complex disease states such as cancer. We focus this review on these emerging functions in order to define the true roles of neutrophils in homeostasis, immunity, and disease.

Teaser

Classically viewed as homogeneous effector cells with poor regulatory functions, neutrophils are now known to be phenotypically and functionally diverse. Nicolás-Ávila and colleagues review these emerging properties and discuss how neutrophils contribute to homeostasis, immune defense, and disease.

GM-CSF: From Growth Factor to Central Mediator of Tissue Inflammation

15 November 2016

Publication date: 15 November 2016
Source:Immunity, Volume 45, Issue 5

Author(s): Burkhard Becher, Sonia Tugues, Melanie Greter

The granulocyte-macrophage colony-stimulating factor (GM-CSF) was initially classified as a hematopoietic growth factor. However, unlike its close relatives macrophage CSF (M-CSF) and granulocyte CSF (G-CSF), the majority of myeloid cells do not require GM-CSF for steady-state myelopoiesis. Instead, in inflammation, GM-CSF serves as a communication conduit between tissue-invading lymphocytes and myeloid cells. Even though lymphocytes are in all likelihood the instigators of chronic inflammatory disease, GM-CSF-activated phagocytes are well equipped to cause tissue damage. The pivotal role of GM-CSF at the T cell:myeloid cell interface might shift our attention toward studying the function of the myeloid compartment in immunopathology. Targeting specifically the crosstalk between T cells and myeloid cells through GM-CSF holds promise for the development of therapeutics to combat chronic tissue inflammation. Here, we will review some of the major discoveries of the recent past, which indicate that GM-CSF is so much more than its name suggests.

Teaser

GM-CSF has initially been categorized as a hematopoietic growth factor involved in steady-state myelopoiesis. However, it now emerges as a critical communication conduit between lymphocytes and myeloid cells in inflammation. Becher and colleagues discuss recent developments showing that, through its activity on myeloid cells, GM-CSF plays a key role in immunopathology.

Functions of Murine Dendritic Cells

18 October 2016

Publication date: 18 October 2016
Source:Immunity, Volume 45, Issue 4

Author(s): Vivek Durai, Kenneth M. Murphy

Dendritic cells (DCs) play critical roles in activating innate immune cells and initiating adaptive immune responses. The functions of DCs were originally obscured by their overlap with other mononuclear phagocytes, but new mouse models have allowed for the selective ablation of subsets of DCs and have helped to identify their non-redundant roles in the immune system. These tools have elucidated the functions of DCs in host defense against pathogens, autoimmunity, and cancer. This review will describe the mouse models generated to interrogate the role of DCs and will discuss how their use has progressively clarified our understanding of the unique functions of DC subsets.

Teaser

Durai and Murphy (2016) review the progress made in developing new mouse models for the analysis of the functions of dendritic cell subsets and what these models have revealed about the roles of these cells in immune responses.

Germinal Center B Cell Dynamics

20 September 2016

Publication date: 20 September 2016
Source:Immunity, Volume 45, Issue 3

Author(s): Luka Mesin, Jonatan Ersching, Gabriel D. Victora

Germinal centers (GCs) are the site of antibody diversification and affinity maturation and as such are vitally important for humoral immunity. The study of GC biology has undergone a renaissance in the past 10 years, with a succession of findings that have transformed our understanding of the cellular dynamics of affinity maturation. In this review, we discuss recent developments in the field, with special emphasis on how GC cellular and clonal dynamics shape antibody affinity and diversity during the immune response.

Teaser

Germinal centers are ultrastructural sites within lymphoid tissue that support the maturation of B lymphocytes into antibody-secreting cells. In this review, Mesin et al. update the current understanding of the cellular interactions and positioning of B lymphocytes within these foci to support a humoral immune response.

Complement-Mediated Regulation of Metabolism and Basic Cellular Processes

16 August 2016

Publication date: 16 August 2016
Source:Immunity, Volume 45, Issue 2

Author(s): Christoph Hess, Claudia Kemper

Complement is well appreciated as a critical arm of innate immunity. It is required for the removal of invading pathogens and works by directly destroying them through the activation of innate and adaptive immune cells. However, complement activation and function is not confined to the extracellular space but also occurs within cells. Recent work indicates that complement activation regulates key metabolic pathways and thus can impact fundamental cellular processes, such as survival, proliferation, and autophagy. Newly identified functions of complement include a key role in shaping metabolic reprogramming, which underlies T cell effector differentiation, and a role as a nexus for interactions with other effector systems, in particular the inflammasome and Notch transcription-factor networks. This review focuses on the contributions of complement to basic processes of the cell, in particular the integration of complement with cellular metabolism and the potential implications in infection and other disease settings.

Teaser

Serum-circulating complement is critical for protection against invading pathogens. However, it is becoming increasingly clear that the complement system serves additional “non-classical” roles. Hess and Kemper discuss newly described intracellular and autocrine functions of complement in the regulation of metabolism and basic cellular processes.

Post-Translational Modification Control of Innate Immunity

19 July 2016

Publication date: 19 July 2016
Source:Immunity, Volume 45, Issue 1

Author(s): Juan Liu, Cheng Qian, Xuetao Cao

A coordinated balance between the positive and negative regulation of pattern-recognition receptor (PRR)-initiated innate inflammatory responses is required to ensure the most favorable outcome for the host. Post-translational modifications (PTMs) of innate sensors and downstream signaling molecules influence their activity and function by inducing their covalent linkage to new functional groups. PTMs including phosphorylation and polyubiquitination have been shown to potently regulate innate inflammatory responses through the activation, cellular translocation, and interaction of innate receptors, adaptors, and downstream signaling molecules in response to infectious and dangerous signals. Other PTMs such as methylation, acetylation, SUMOylation, and succinylation are increasingly implicated in the regulation of innate immunity and inflammation. In this review, we focus on the roles of PTMs in controlling PRR-triggered innate immunity and inflammatory responses. The emerging roles of PTMs in the pathogenesis and potential treatment of infectious and inflammatory immune diseases are also discussed.

Teaser

Post-translational modifications (PTMs) of innate sensors and downstream signaling molecules influence their activity and function, and this regulation is crucial to maintain host immunity. Cao and colleagues discuss the emerging roles of PTMs in the pathogenesis and potential treatment of infectious and inflammatory immune diseases.

Resistance Mechanisms to Immune-Checkpoint Blockade in Cancer: Tumor-Intrinsic and -Extrinsic Factors

21 June 2016

Publication date: 21 June 2016
Source:Immunity, Volume 44, Issue 6

Author(s): Jonathan M. Pitt, Marie Vétizou, Romain Daillère, María Paula Roberti, Takahiro Yamazaki, Bertrand Routy, Patricia Lepage, Ivo Gomperts Boneca, Mathias Chamaillard, Guido Kroemer, Laurence Zitvogel

Inhibition of immune regulatory checkpoints, such as CTLA-4 and the PD-1-PD-L1 axis, is at the forefront of immunotherapy for cancers of various histological types. However, such immunotherapies fail to control neoplasia in a significant proportion of patients. Here, we review how a range of cancer-cell-autonomous cues, tumor-microenvironmental factors, and host-related influences might account for the heterogeneous responses and failures often encountered during therapies using immune-checkpoint blockade. Furthermore, we describe the emerging evidence of how the strong interrelationship between the immune system and the host microbiota can determine responses to cancer therapies, and we introduce a concept by which prior or concomitant modulation of the gut microbiome could optimize therapeutic outcomes upon immune-checkpoint blockade.

Teaser

Immune-checkpoint blockers are at the forefront of cancer immunotherapy, yet they fail to control neoplasia in most patients. Pitt et al. discuss the diverse influences responsible for the heterogeneity in treatment responses by focusing on the newfound impact of host microbiota.

Coinhibitory Pathways in the B7-CD28 Ligand-Receptor Family

17 May 2016

Publication date: 17 May 2016
Source:Immunity, Volume 44, Issue 5

Author(s): Frank A. Schildberg, Sarah R. Klein, Gordon J. Freeman, Arlene H. Sharpe

Immune responses need to be controlled for optimal protective immunity and tolerance. Coinhibitory pathways in the B7-CD28 family provide critical inhibitory signals that regulate immune homeostasis and defense and protect tissue integrity. These coinhibitory signals limit the strength and duration of immune responses, thereby curbing immune-mediated tissue damage, regulating resolution of inflammation, and maintaining tolerance to prevent autoimmunity. Tumors and microbes that cause chronic infections can exploit these coinhibitory pathways to establish an immunosuppressive microenvironment, hindering their eradication. Advances in understanding T cell coinhibitory pathways have stimulated a new era of immunotherapy with effective drugs to treat cancer, autoimmune and infectious diseases, and transplant rejection. In this review we discuss the current knowledge of the mechanisms underlying the coinhibitory functions of pathways in the B7-CD28 family, the diverse functional consequences of these inhibitory signals on immune responses, and the overlapping and unique functions of these key immunoregulatory pathways.

Teaser

Coinhibitory pathways in the B7-CD28 family provide critical inhibitory signals that regulate immune homeostasis and defense. Sharpe and colleagues discuss the current understanding of mechanisms underlying the coinhibitory functions of pathways in the B7-CD28 family, their functional consequences, and their overlapping and unique functions.

CD28 Costimulation: From Mechanism to Therapy

17 May 2016

Publication date: 17 May 2016
Source:Immunity, Volume 44, Issue 5

Author(s): Jonathan H. Esensten, Ynes A. Helou, Gaurav Chopra, Arthur Weiss, Jeffrey A. Bluestone

Ligation of the CD28 receptor on T cells provides a critical second signal alongside T cell receptor (TCR) ligation for naive T cell activation. Here, we discuss the expression, structure, and biochemistry of CD28 and its ligands. CD28 signals play a key role in many T cell processes, including cytoskeletal remodeling, production of cytokines, survival, and differentiation. CD28 ligation leads to unique epigenetic, transcriptional, and post-translational changes in T cells that cannot be recapitulated by TCR ligation alone. We discuss the function of CD28 and its ligands in both effector and regulatory T cells. CD28 is critical for regulatory T cell survival and the maintenance of immune homeostasis. We outline the roles that CD28 and its family members play in human disease and we review the clinical efficacy of drugs that block CD28 ligands. Despite the centrality of CD28 and its family members and ligands to immune function, many aspects of CD28 biology remain unclear. Translation of a basic understanding of CD28 function into immunomodulatory therapeutics has been uneven, with both successes and failures. Such real-world results might stem from multiple factors, including complex receptor-ligand interactions among CD28 family members, differences between the mouse and human CD28 families, and cell-type specific roles of CD28 family members.

Teaser

The CD28 receptor and its ligands are critical for effector and regulatory T cell function. Bluestone and colleagues review the expression, structure, and biochemistry of CD28 and its ligands in T cells. The review also discusses the roles of CD28 in human disease and in patients treated with drugs that target this receptor-ligand system.

Lag-3, Tim-3, and TIGIT: Co-inhibitory Receptors with Specialized Functions in Immune Regulation

17 May 2016

Publication date: 17 May 2016
Source:Immunity, Volume 44, Issue 5

Author(s): Ana C. Anderson, Nicole Joller, Vijay K. Kuchroo

Co-inhibitory receptors, such as CTLA-4 and PD-1, have an important role in regulating T cell responses and have proven to be effective targets in the setting of chronic diseases where constitutive co-inhibitory receptor expression on T cells dampens effector T cell responses. Unfortunately, many patients still fail to respond to therapies that target CTLA-4 and PD-1. The next wave of co-inhibitory receptor targets that are being explored in clinical trials include Lag-3, Tim-3, and TIGIT. These receptors, although they belong to the same class of receptors as PD-1 and CTLA-4, exhibit unique functions, especially at tissue sites where they regulate distinct aspects of immunity. Increased understanding of the specialized functions of these receptors will inform the rational application of therapies that target these receptors to the clinic.

Teaser

The next wave of co-inhibitory receptor targets for immunotherapy has specialized roles in regulating diverse aspects of the immune response. Understanding these roles is critical for incorporating therapies against these receptors into the current immunotherapy landscape.

The TNF Receptor Superfamily in Co-stimulating and Co-inhibitory Responses

17 May 2016

Publication date: 17 May 2016
Source:Immunity, Volume 44, Issue 5

Author(s): Lindsay K. Ward-Kavanagh, Wai Wai Lin, John R. Šedý, Carl F. Ware

Cytokines related to tumor necrosis factor (TNF) provide a communication network essential for coordinating multiple cell types into an effective host defense system against pathogens and malignant cells. The pathways controlled by the TNF superfamily differentiate both innate and adaptive immune cells and modulate stromal cells into microenvironments conducive to host defenses. Members of the TNF receptor superfamily activate diverse cellular functions from the production of type 1 interferons to the modulation of survival of antigen-activated T cells. Here, we focus attention on the subset of TNF superfamily receptors encoded in the immune response locus in chromosomal region 1p36. Recent studies have revealed that these receptors use diverse mechanisms to either co-stimulate or restrict immune responses. Translation of the fundamental mechanisms of TNF superfamily is leading to the design of therapeutics that can alter pathogenic processes in several autoimmune diseases or promote immunity to tumors.

Teaser

A deeper understanding of the network of cellular and molecular pathways initiated by the TNF superfamily of cytokines is emerging from fundamental research and human clinical trials. Selective modulation of these cytokines could achieve the goal of limiting cancer without autoimmune disease as a restricting consequence.

T Cell Cosignaling Molecules in Transplantation

17 May 2016

Publication date: 17 May 2016
Source:Immunity, Volume 44, Issue 5

Author(s): Mandy L. Ford

The ultimate outcome of alloreactivity versus tolerance following transplantation is potently influenced by the constellation of cosignaling molecules expressed by immune cells during priming with alloantigen, and the net sum of costimulatory and coinhibitory signals transmitted via ligation of these molecules. Intense investigation over the last two decades has yielded a detailed understanding of the kinetics, cellular distribution, and intracellular signaling networks of cosignaling molecules such as the CD28, TNF, and TIM families of receptors in alloimmunity. More recent work has better defined the cellular and molecular mechanisms by which engagement of cosignaling networks serve to either dampen or augment alloimmunity. These findings will likely aid in the rational development of novel immunomodulatory strategies to prolong graft survival and improve outcomes following transplantation.

Teaser

Transplantation is a life-saving therapy for end-stage organ disease, yet the alloreactive T cell response poses a significant barrier to long-term graft survival. Seminal studies and emerging findings have defined the roles that T cell costimulatory and coinhibitory receptors play in tipping the balance between transplant rejection and tolerance.

Co-stimulatory and Co-inhibitory Pathways in Autoimmunity

17 May 2016

Publication date: 17 May 2016
Source:Immunity, Volume 44, Issue 5

Author(s): Qianxia Zhang, Dario A.A. Vignali

The immune system is guided by a series of checks and balances, a major component of which is a large array of co-stimulatory and co-inhibitory pathways that modulate the host response. Although co-stimulation is essential for boosting and shaping the initial response following signaling through the antigen receptor, inhibitory pathways are also critical for modulating the immune response. Excessive co-stimulation and/or insufficient co-inhibition can lead to a breakdown of self-tolerance and thus to autoimmunity. In this review, we will focus on the role of co-stimulatory and co-inhibitory pathways in two systemic (systemic lupus erythematosus and rheumatoid arthritis) and two organ-specific (multiple sclerosis and type 1 diabetes) emblematic autoimmune diseases. We will also discuss how mechanistic analysis of these pathways has led to the identification of potential therapeutic targets and initiation of clinical trials for autoimmune diseases, as well as outline some of the challenges that lie ahead.

Teaser

Co-stimulatory and co-inhibitory receptors are major modulators of the immune response in health and disease. Zhang and Vignali review our current understanding of the impact of co-stimulatory and co-inhibitory receptors in four emblematic autoimmune diseases and outline the challenges of developing effective therapies for such diseases.

Costimulatory and Coinhibitory Receptor Pathways in Infectious Disease

17 May 2016

Publication date: 17 May 2016
Source:Immunity, Volume 44, Issue 5

Author(s): John Attanasio, E. John Wherry

Costimulatory and inhibitory receptors play a key role in regulating immune responses to infections. Recent translation of knowledge about inhibitory receptors such as CTLA-4 and PD-1 into the cancer clinic highlights the opportunities to manipulate these pathways to treat human disease. Studies in infectious disease have provided key insights into the specific roles of these pathways and the effects of their manipulation. Here, recent studies are discussed that have addressed how major inhibitory and costimulatory pathways play a role in regulating immune responses during acute and chronic infections. Mechanistic insights from studies of infectious disease provide opportunities to further expand our toolkit to treat cancer and chronic infections in the clinic.

Teaser

Costimulatory and inhibitory receptors play key roles in regulating immune responses to infection. Attanasio and Wherry reviews how insights from these infectious systems have provided insights into the biology of pathways such as PD-1 and how these insights inform clinical therapeutic targeting of these pathways in infectious disease and cancer.

Targeting T Cell Co-receptors for Cancer Therapy

17 May 2016

Publication date: 17 May 2016
Source:Immunity, Volume 44, Issue 5

Author(s): Margaret K. Callahan, Michael A. Postow, Jedd D. Wolchok

Checkpoint-blocking antibodies can generate potent anti-tumor responses by encouraging the immune system to seek and destroy cancer cells. At this time, the United States Food and Drug Administration has approved three checkpoint-blocking antibodies in three disease indications, and additional approvals are expected to broaden the clinical scope of immunotherapy. Herein, we review the clinical development of CTLA-4-, PD-1-, and PD-L1-blocking antibodies across tumor types and briefly discuss areas of active investigation of potential biomarkers.

Teaser

Targeting molecules that regulate T cell activity is an approach that has been translated into potent cancer therapies. Callahan, Postow, and Wolchok review the clinical development of PD-1-, PD-L1-, and CTLA-4-blocking antibodies. They review the clinical activity of agents in development and toxicities associated with this novel approach and summarize recent developments in the search for biomarkers to guide the clinical use of these drugs.

The Microbiome, Timing, and Barrier Function in the Context of Allergic Disease

19 April 2016

Publication date: 19 April 2016
Source:Immunity, Volume 44, Issue 4

Author(s): Duane R. Wesemann, Cathryn R. Nagler

Allergic disease affects millions. Despite many advances in our understanding of the immune system in the past century, the physiologic underpinning for the existence of allergy remains largely mysterious. Food allergies, in particular, have increased dramatically in recent years, adding a new sense of urgency to unraveling this mystery. The concurrence of significant lifestyle changes in Western societies with increasing disease prevalence implies a causal link. Demographic variables that influence the composition and function of the commensal microbiota early in life seem to be most important. Identifying the evolutionary and physiologic foundations of allergic disease and defining what about our modern environment is responsible for its increased incidence will provide insights critical to the development of new approaches to prevention and treatment.

Teaser

The rising prevalence of allergic disease is an increasing public health concern. Wesemann and Nagler discuss emerging ideas regarding the physiologic foundations of allergy. They examine evidence for the roles of the microbiome, timing of environmental exposures, and barrier function in disease manifestation and integrate these findings into a barrier regulation hypothesis of allergy.