Advances In Immunology[JOURNAL]
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200 papers
Chromatin Interactions in the Control of Immunoglobulin Heavy Chain Gene Assembly.
Kumari G, Sen R
Adv Immunol · 2015 · PMID 26477365 · Publisher ↗
Expression of antibody heavy chain occurs via precisely timed developmental activation of the immunoglobulin heavy chain (IgH) gene locus during B cell development. IgH locus activation permits coordinated gene rearrange...
Expression of antibody heavy chain occurs via precisely timed developmental activation of the immunoglobulin heavy chain (IgH) gene locus during B cell development. IgH locus activation permits coordinated gene rearrangements that assemble variable (VH), diversity (DH), and joining (JH) gene segments into functional genes. Chromosomal conformation changes and epigenetic mechanisms play critical roles in ensuring rearrangement fidelity while minimizing hazardous consequences of broken DNA ends generated during recombination. In this review, we summarize the current status of regulatory mechanisms that underpin effective IgH gene assembly. For this, the germline locus is divided into two parts: a 2.4Mb 5' part that contains all VH gene segments and a 300kb 3' domain that contains DH and JH gene segments, as well as exons that encode IgH isotypes. Structural features of each part are discussed individually, followed by consideration of how the two parts come together to complete IgH recombination. Throughout we emphasize current insights, propose plausible mechanisms, and highlight key questions for future studies.
Regulation and Evolution of the RAG Recombinase.
Teng G, Schatz DG
Adv Immunol · 2015 · PMID 26477364 · Publisher ↗
The modular, noncontiguous architecture of the antigen receptor genes necessitates their assembly through V(D)J recombination. This program of DNA breakage and rejoining occurs during early lymphocyte development, and de...
The modular, noncontiguous architecture of the antigen receptor genes necessitates their assembly through V(D)J recombination. This program of DNA breakage and rejoining occurs during early lymphocyte development, and depends on the RAG1 and RAG2 proteins, whose collaborative endonuclease activity targets specific DNA motifs enriched in the antigen receptor loci. This essential gene shuffling reaction requires lymphocytes to traverse several developmental stages wherein DNA breakage is tolerated, while minimizing the expense to overall genome integrity. Thus, RAG activity is subject to stringent temporal and spatial regulation. The RAG proteins themselves also contribute autoregulatory properties that coordinate their DNA cleavage activity with target chromatin structure, cell cycle status, and DNA repair pathways. Even so, lapses in regulatory restriction of RAG activity are apparent in the aberrant V(D)J recombination events that underlie many lymphomas. In this review, we discuss the current understanding of the RAG endonuclease, its widespread binding in the lymphocyte genome, its noncleavage activities that restrain its enzymatic potential, and the growing evidence of its evolution from an ancient transposase.
RNA Exosome Regulates AID DNA Mutator Activity in the B Cell Genome.
Pefanis E, Basu U
Adv Immunol · 2015 · PMID 26073986 · Full text
The immunoglobulin diversification processes of somatic hypermutation and class switch recombination critically rely on transcription-coupled targeting of activation-induced cytidine deaminase (AID) to Ig loci in activat...
The immunoglobulin diversification processes of somatic hypermutation and class switch recombination critically rely on transcription-coupled targeting of activation-induced cytidine deaminase (AID) to Ig loci in activated B lymphocytes. AID catalyzes deamination of cytidine deoxynucleotides on exposed single-stranded DNA. In addition to driving immunoglobulin diversity, promiscuous targeting of AID mutagenic activity poses a deleterious threat to genomic stability. Recent genome-wide studies have uncovered pervasive AID activity throughout the B cell genome. It is increasingly apparent that AID activity is frequently targeted to genomic loci undergoing early transcription termination where RNA exosome promotes the resolution of stalled transcription complexes via cotranscriptional RNA degradation mechanisms. Here, we review aspects and consequences of eukaryotic transcription that lead to early termination, RNA exosome recruitment, and ultimately targeting of AID mutagenic activity.
IgE and Mast Cells: The Endogenous Adjuvant.
Oettgen HC, Burton OT
Adv Immunol · 2015 · PMID 26073985 · Publisher ↗
Mast cells and immunoglobulin E (IgE) are most familiar as the effectors of type I hypersensitivity reactions including anaphylaxis. It is becoming clear however that this pair has important immunomodulatory effects on i...
Mast cells and immunoglobulin E (IgE) are most familiar as the effectors of type I hypersensitivity reactions including anaphylaxis. It is becoming clear however that this pair has important immunomodulatory effects on innate and adaptive cells of the immune system. In this purview, they act as endogenous adjuvants to ignite evolving immune responses, promote the transition of allergic disease into chronic illness, and disrupt the development of active mechanisms of tolerance to ingested foods. Suppression of IgE-mediated mast cell activation can be exerted by molecules targeting IgE, FcɛRI, or signaling kinases including Syk, or by IgG antibodies acting via inhibitory Fcγ receptors. Recent reports indicate that such interventions have promise in the development of strategies to treat allergic disease.
Activation and Function of iNKT and MAIT Cells.
Chandra S, Kronenberg M
Adv Immunol · 2015 · PMID 26073984 · Publisher ↗
Over the last two decades, it has been established that peptides are not the only antigens recognized by T lymphocytes. Here, we review information on two T lymphocyte populations that recognize nonpeptide antigens: inva...
Over the last two decades, it has been established that peptides are not the only antigens recognized by T lymphocytes. Here, we review information on two T lymphocyte populations that recognize nonpeptide antigens: invariant natural killer T cells (iNKT cells), which respond to glycolipids, and mucosal associated invariant T cells (MAIT cells), which recognize microbial metabolites. These two populations have a number of striking properties that distinguish them from the majority of T cells. First, their cognate antigens are presented by nonclassical class I antigen-presenting molecules; CD1d for iNKT cells and MR1 for MAIT cells. Second, these T lymphocyte populations have a highly restricted diversity of their T cell antigen receptor α chains. Third, these cells respond rapidly to antigen or cytokine stimulation by producing copious amounts of cytokines, such as IFNγ, which normally are only made by highly differentiated effector T lymphocytes. Because of their response characteristics, iNKT and MAIT cells act at the interface of innate and adaptive immunity, participating in both types of responses. In this review, we will compare these two subsets of innate-like T cells, with an emphasis on the various ways that lead to their activation and their participation in antimicrobial responses.
HLA-G: An Immune Checkpoint Molecule.
Carosella ED, Rouas-Freiss N, Tronik-Le Roux D … +2 more , Moreau P, LeMaoult J
Adv Immunol · 2015 · PMID 26073983 · Publisher ↗
HLA-G is a molecule that was first known to confer protection to the fetus from destruction by the immune system of its mother, thus critically contributing to fetal-maternal tolerance. The first functional finding const...
HLA-G is a molecule that was first known to confer protection to the fetus from destruction by the immune system of its mother, thus critically contributing to fetal-maternal tolerance. The first functional finding constituted the basis for HLA-G research and can be summarized as such: HLA-G, membrane-bound or soluble, strongly binds its inhibitory receptors on immune cells (NK, T, B, monocytes/dendritic cells), inhibits the functions of these effectors, and so induces immune inhibition. HLA-G function may therefore be beneficial because when expressed by a fetus or a transplant it protects them from rejection, or deleterious because when expressed by a tumor, it also protects it from antitumor immunity. This is the primary HLA-G function: that of a checkpoint molecule. Great work has been done in the past years to characterize HLA-G itself, its regulation, its functions and mechanisms of action, and its pathological relevance. We will review this here, focusing on transplantation and oncology because these pathological contexts have been studied the most and also because they best represent the two opposite sides of HLA-G: beneficial to be promoted, or deleterious to be blocked.
Cross-Presentation in Mouse and Human Dendritic Cells.
Segura E, Amigorena S
Adv Immunol · 2015 · PMID 26073982 · Publisher ↗
Cross-presentation designates the presentation of exogenous antigens on major histocompatibility complex class I molecules and is essential for the initiation of cytotoxic immune responses. It is now well established tha...
Cross-presentation designates the presentation of exogenous antigens on major histocompatibility complex class I molecules and is essential for the initiation of cytotoxic immune responses. It is now well established that dendritic cells (DCs) are the best cross-presenting cells. In this chapter, we will discuss recent advances in our understanding of the molecular mechanisms of cross-presentation. We will also describe the different DC subsets identified in mouse and human, and their functional specialization for cross-presentation. Finally, we will summarize the current knowledge of the role of cross-presentation in pathological situations.
Innate memory T cells.
Jameson SC, Lee YJ, Hogquist KA
Adv Immunol · 2015 · PMID 25727290 · Full text
Memory T cells are usually considered to be a feature of a successful immune response against a foreign antigen, and such cells can mediate potent immunity. However, in mice, alternative pathways have been described, thr...
Memory T cells are usually considered to be a feature of a successful immune response against a foreign antigen, and such cells can mediate potent immunity. However, in mice, alternative pathways have been described, through which naïve T cells can acquire the characteristics and functions of memory T cells without encountering specific foreign antigen or the typical signals required for conventional T cell differentiation. Such cells reflect a response to the internal rather the external environment, and hence such cells are called innate memory T cells. In this review, we describe how innate memory subsets were identified, the signals that induce their generation and their functional properties and potential role in the normal immune response. The existence of innate memory T cells in mice raises questions about whether parallel populations exist in humans, and we discuss the evidence for such populations during human T cell development and differentiation.
Epithelial cell contributions to intestinal immunity.
Hooper LV
Adv Immunol · 2015 · PMID 25727289 · Publisher ↗
The epithelial surfaces of the mammalian intestine interface directly with the external environment and thus continuously encounter pathogenic bacteria, fungi, viruses, and parasites. The intestinal epithelium is also cl...
The epithelial surfaces of the mammalian intestine interface directly with the external environment and thus continuously encounter pathogenic bacteria, fungi, viruses, and parasites. The intestinal epithelium is also closely associated with complex communities of symbiotic microorganisms. Intestinal epithelial cells are thus faced with the unique challenge of directly interacting with enormous numbers of microbes that include both pathogens and symbionts. As a result, gut epithelia have evolved an array of strategies that contribute to host immunity. This chapter considers the various mechanisms used by epithelial cells to limit microbial invasion of host tissues, shape the composition of indigenous microbial communities, and coordinate the adaptive immune response to microorganisms. Study of intestinal epithelial cells has contributed fundamental insights into intestinal immune homeostasis and has revealed how impaired epithelial cell function can contribute to inflammatory disease.
Approaches for analyzing the roles of mast cells and their proteases in vivo.
Galli SJ, Tsai M, Marichal T … +3 more , Tchougounova E, Reber LL, Pejler G
Adv Immunol · 2015 · PMID 25727288 · Full text
The roles of mast cells in health and disease remain incompletely understood. While the evidence that mast cells are critical effector cells in IgE-dependent anaphylaxis and other acute IgE-mediated allergic reactions se...
The roles of mast cells in health and disease remain incompletely understood. While the evidence that mast cells are critical effector cells in IgE-dependent anaphylaxis and other acute IgE-mediated allergic reactions seems unassailable, studies employing various mice deficient in mast cells or mast cell-associated proteases have yielded divergent conclusions about the roles of mast cells or their proteases in certain other immunological responses. Such "controversial" results call into question the relative utility of various older versus newer approaches to ascertain the roles of mast cells and mast cell proteases in vivo. This review discusses how both older and more recent mouse models have been used to investigate the functions of mast cells and their proteases in health and disease. We particularly focus on settings in which divergent conclusions about the importance of mast cells and their proteases have been supported by studies that employed different models of mast cell or mast cell protease deficiency. We think that two major conclusions can be drawn from such findings: (1) no matter which models of mast cell or mast cell protease deficiency one employs, the conclusions drawn from the experiments always should take into account the potential limitations of the models (particularly abnormalities affecting cell types other than mast cells) and (2) even when analyzing a biological response using a single model of mast cell or mast cell protease deficiency, details of experimental design are critical in efforts to define those conditions under which important contributions of mast cells or their proteases can be identified.
NOD.H-2h4 mice: an important and underutilized animal model of autoimmune thyroiditis and Sjogren's syndrome.
Braley-Mullen H, Yu S
Adv Immunol · 2015 · PMID 25727287 · Publisher ↗
NOD.H-2h4 mice express the K haplotype on the NOD genetic background. They spontaneously develop thyroiditis and Sjogren's syndrome, but they do not develop diabetes. Although autoimmune thyroid diseases and Sjogren's sy...
NOD.H-2h4 mice express the K haplotype on the NOD genetic background. They spontaneously develop thyroiditis and Sjogren's syndrome, but they do not develop diabetes. Although autoimmune thyroid diseases and Sjogren's syndrome are highly prevalent autoimmune diseases in humans, there has been relatively little emphasis on the use of animal models of these diseases for understanding basic mechanisms involved in development and therapy of chronic organ-specific autoimmune diseases. The goal of this review is to highlight some of the advantages of NOD.H-2h4 mice for studying basic mechanisms involved in development of autoimmunity. NOD.H-2h4 mice are one of relatively few animal models that develop organ-specific autoimmune diseases spontaneously, i.e., without a requirement for immunization with antigen and adjuvant, and in both sexes in a relatively short period of time. Thyroiditis and Sjogren's syndrome in NOD.H-2h4 mice are chronic autoimmune diseases that develop relatively early in life and persist for the life of the animal. Because the animals do not become clinically ill, the NOD.H-2h4 mouse provides an excellent model to test therapeutic protocols over a long period of time. The availability of several mutant mice on this background provides a means to address the impact of particular cells and molecules on the autoimmune diseases. Moreover, to our knowledge, this is the only animal model in which the presence or absence of a single cytokine, IFN-γ, is sufficient to completely inhibit one autoimmune thyroid disease, with a completely distinct autoimmune thyroid disease developing when it is absent.
Microbes and B cell development.
Wesemann DR
Adv Immunol · 2015 · PMID 25591467 · Publisher ↗
Animals and many of their chronic microbial inhabitants form relationships of symbiotic mutualism, which occurs when coexisting life-forms derive mutual benefit from stable associations. While microorganisms receive a se...
Animals and many of their chronic microbial inhabitants form relationships of symbiotic mutualism, which occurs when coexisting life-forms derive mutual benefit from stable associations. While microorganisms receive a secure habitat and constant food source from vertebrate hosts, they are required for optimal immune system development and occupy niches otherwise abused by pathogens. Microbes have also been shown to provide vertebrate hosts with metabolic capabilities that enhance energy and nutrient uptake from the diet. The immune system plays a central role in the establishment and maintenance of host-microbe homeostasis, and B lineage cells play a key role in this regulation. Here, I reviewed the structure and function of the microbiota and the known mechanisms of how nonpathogenic microbes influence B cell biology and immunoglobulin repertoire development early in life. I also discuss what is known about how B lineage cells contribute to the process of shaping the composition of commensal/mutualistic microbe membership.
Group 2 innate lymphoid cells in the regulation of immune responses.
Roediger B, Weninger W
Adv Immunol · 2015 · PMID 25591466 · Publisher ↗
Type 2 cytokine-driven immune responses are important against parasite infections but also underlie the development of inflammatory allergic diseases. Type 2 CD4(+) T (Th2) cells have long been believed to act as central...
Type 2 cytokine-driven immune responses are important against parasite infections but also underlie the development of inflammatory allergic diseases. Type 2 CD4(+) T (Th2) cells have long been believed to act as central regulators of allergic conditions via the production of the signature cytokines IL-4, IL-5, and IL-13. However, the more recent identification of group 2 innate lymphoid cells ILC (ILC2) cells, which also produce the same cytokines, necessitates a reevaluation of the relative roles these two populations play during type 2 inflammation. ILC2 cells preferentially localize to the interface between the host and the environment (lung, intestine, skin) and respond to epithelium-derived cytokines associated with barrier disruption, such as IL-25, IL-33, and thymic stromal lymphopoietin. ILC2 cells are a major source of IL-5 and IL-13 in vivo but may also produce IL-4 and IL-9 under more defined conditions. ILC2 cells regulate local inflammatory responses to environmental challenges, and this in turn enables them to influence downstream adaptive immune responses. Here, we discuss our current understanding of ILC2 cell phenotype, development and function, and detail the expanding array of cell surface receptor and signaling pathways that enable ILC2 cells to perform a variety of biological functions in vivo. We give special attention to the most recently described and poorly understood member of the ILC2 cell family, the dermal ILC2 cells, and discuss their role in regulating skin inflammation.
Positive-selection-inducing self-peptides displayed by cortical thymic epithelial cells.
Takada K, Takahama Y
Adv Immunol · 2015 · PMID 25591465 · Publisher ↗
A repertoire of antigen recognition specificities in mature T cell pool is formed by the selection during T cell development in the thymus. Positive selection is an essential process for the development of functionally c...
A repertoire of antigen recognition specificities in mature T cell pool is formed by the selection during T cell development in the thymus. Positive selection is an essential process for the development of functionally competent T cells and is dependent on the interaction between T cell antigen receptors (TCRs) that newly generated thymocytes express and self-peptide-associated major histocompatibility complex (pMHC) molecules that cortical thymic epithelial cells (cTECs) express. Characterization of positive-selection-inducing peptides has revealed that the low-affinity TCR engagement by the positive-selection-inducing pMHC complexes initiates intracellular signals that induce the survival of immature thymocytes and their differentiation into mature T cells. Recent studies suggest unique mechanisms of antigen processing in cTECs for the production of positively selecting MHC-bound self-peptides.
Mast cells' integrated actions with eosinophils and fibroblasts in allergic inflammation: implications for therapy.
Landolina N, Gangwar RS, Levi-Schaffer F
Adv Immunol · 2015 · PMID 25591464 · Publisher ↗
Mast cells (MCs) and eosinophils (Eos) are the key players in the development of allergic inflammation (AI). Their cross-talk, named the Allergic Effector Unit (AEU), takes place through an array of soluble mediators and...
Mast cells (MCs) and eosinophils (Eos) are the key players in the development of allergic inflammation (AI). Their cross-talk, named the Allergic Effector Unit (AEU), takes place through an array of soluble mediators and ligands/receptors interactions that enhance the functions of both the cells. One of the salient features of the AEU is the CD48/2B4 receptor/ligand binding complex. Furthermore, MCs and Eos have been demonstrated to play a role not only in AI but also in the modulation of its consequence, i.e., fibrosis/tissue remodeling, by directly influencing fibroblasts (FBs), the main target cells of these processes. In turn, FBs can regulate the survival, activity, and phenotype of both MCs and Eos. Therefore, a complex three players, MCs/Eos/FBs interaction, can take place in various stages of AI. The characterization of the soluble and physical mediated cross talk among these three cells might lead to the identification of both better and novel targets for the treatment of allergy and its tissue remodeling consequences.
Regulation of CD4 and CD8 coreceptor expression and CD4 versus CD8 lineage decisions.
Egawa T
Adv Immunol · 2015 · PMID 25591463 · Publisher ↗
During blood cell development, hematopoietic stem cells generate diverse mature populations via several rounds of binary fate decisions. At each bifurcation, precursors adopt one fate and inactivate the alternative fate...
During blood cell development, hematopoietic stem cells generate diverse mature populations via several rounds of binary fate decisions. At each bifurcation, precursors adopt one fate and inactivate the alternative fate either stochastically or in response to extrinsic stimuli and stably maintain the selected fates. Studying of these processes would contribute to better understanding of etiology of immunodeficiency and leukemia, which are caused by abnormal gene regulation during the development of hematopoietic cells. The CD4(+) helper versus CD8(+) cytotoxic T-cell fate decision serves as an excellent model to study binary fate decision processes. These two cell types are derived from common precursors in the thymus. Positive selection of their TCRs by self-peptide presented on either MHC class I or class II triggers their fate decisions along with mutually exclusive retention and silencing of two coreceptors, CD4 and CD8. In the past few decades, extensive effort has been made to understand the T-cell fate decision processes by studying regulation of genes encoding the coreceptors and selection processes. These studies have identified several key transcription factors and gene regulatory networks. In this chapter, I will discuss recent advances in our understanding of the binary cell fate decision processes of T cells.
Regulation of regulatory T cells: epigenetics and plasticity.
Okada M, Hibino S, Someya K … +1 more , Yoshmura A
Adv Immunol · 2014 · PMID 25175778 · Publisher ↗
Regulatory T (Treg) cells, as central mediators of immune suppression, play crucial roles in many aspects of immune system's physiology and pathophysiology. The transcription factor Foxp3 has been characterized as a mast...
Regulatory T (Treg) cells, as central mediators of immune suppression, play crucial roles in many aspects of immune system's physiology and pathophysiology. The transcription factor Foxp3 has been characterized as a master gene of Tregs. Yet Treg cells possess a distinct pattern of gene expression, including upregulation of immune-suppressive genes and silencing of inflammatory cytokine genes. Recent studies have revealed the molecular mechanisms that establish and maintain such gene regulation in Treg cells. This review discusses recent progress in our understanding of molecular features of Treg cells, with particular attention to Treg-cell lineage commitment and stability.
MHC class I recognition by monocyte-/macrophage-specific receptors.
Yoshida R
Adv Immunol · 2014 · PMID 25175777 · Publisher ↗
The most important transplantation antigens in the discrimination between "self" and "nonself" are encoded by genes in the major histocompatibility complex (MHC) locus (H-2 in mice). It has been assumed that T lymphocyte...
The most important transplantation antigens in the discrimination between "self" and "nonself" are encoded by genes in the major histocompatibility complex (MHC) locus (H-2 in mice). It has been assumed that T lymphocytes are the effector cells for allograft rejection, as athymic nude rodents fail to reject allografts. In 1988, we i.p. transplanted Meth A (H-2D(d)K(d)) tumor cells into C57BL/6 (H-2D(b)K(b)) mice and found macrophages to be cytotoxic against the allografts. In 1996, several groups using CD4 or CD8 knockout mice reported that non-T cells were the effector cells for the rejection of skin or organ allografts. In 1998, we ascertained that macrophages were the effector cells of skin allograft rejection. Recently, we isolated cDNA clones encoding monocyte/macrophage MHC receptors (MMRs) for H-2D(d) and H-2K(d); established H-2D(d)- and/or H-2K(d)-transgenic mice and lymphoma cells; and found, using MMR-deficient mice, that MMR and T-cell receptor were essential for the rejection of transgenic skin and lymphoma, respectively.
Roles for helper T cell lineage-specifying transcription factors in cellular specialization.
Weinmann AS
Adv Immunol · 2014 · PMID 25175776 · Publisher ↗
The development of specialized helper T cells has garnered much attention because of their critical role in coordinating the immune response to invading pathogens. Recent research emphasizing novel functions for speciali...
The development of specialized helper T cells has garnered much attention because of their critical role in coordinating the immune response to invading pathogens. Recent research emphasizing novel functions for specialized helper T cells in a variety of infectious disease settings, as well as autoimmune states, has reshaped our view on the capabilities of helper T cells. Notably, one previously underappreciated aspect of the lifespan of helper T cells is that they often retain the capacity to respond to changes in the environment by altering the composition of helper T cell lineage-specifying transcription factors they express, which, in turn, changes their phenotype. This emerging realization is changing our views on the stability versus flexibility of specialized helper T cell subtypes. Now, there is a new concerted effort to define the mechanistic events that contribute to the potential for flexibility in specialized helper T cell gene expression programs in the different environmental circumstances that allow for the re-expression of helper T cell lineage-specifying transcription factors. In addition, we are also now beginning to appreciate that "helper T cell" lineage-specifying transcription factors are expressed in diverse types of innate and adaptive immune cells and this may allow them to play roles in coordinating aspects of the immune response. Our current challenges include defining the conserved mechanisms that are utilized by these lineage-specifying transcription factors to coordinate gene expression programs in different settings as well as the mechanistic events that contribute to the differential downstream consequences that these factors mediate in unique cellular environments. In this review, we will explore our evolving views on these topics, often times using the Th1-lineage-specifying transcription factor T-bet as an example.
How to trigger a killer: modulation of natural killer cell reactivity on many levels.
Watzl C
Adv Immunol · 2014 · PMID 25175775 · Publisher ↗
The functions of Natural Killer (NK) cells are regulated by a highly redundant set of germline-encoded surface receptors that can inhibit or activate NK cell activities. NK cells can be activated by cytokines or through...
The functions of Natural Killer (NK) cells are regulated by a highly redundant set of germline-encoded surface receptors that can inhibit or activate NK cell activities. NK cells can be activated by cytokines or through the interaction with transformed or infected cells. This typically results in the production of cytokines, chemokines, and the induction of cellular cytotoxicity. However, the reactivity of NK cells is modulated on various levels and shaped by processes such as development, education, priming, exposure to antigens and cytokines, and the formation of memory-like phenotypes. Here, I will summarize our current understanding of these processes and describe how they influence NK cell reactivity on a molecular level.
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