Trends in Immunology

A small jab - a big effect: nonspecific immunomodulation by vaccines.

Publication Date: 2013 May 13 PMID: 23680130
Authors: Benn, C. S. - Netea, M. G. - Selin, L. K. - Aaby, P.
Journal: Trends Immunol

Recent epidemiological studies have shown that, in addition to disease-specific effects, vaccines against infectious diseases have nonspecific effects on the ability of the immune system to handle other pathogens. For instance, in randomized trials tuberculosis and measles vaccines are associated with a substantial reduction in overall child mortality, which cannot be explained by prevention of the target disease. New research suggests that the nonspecific effects of vaccines are related to cross-reactivity of the adaptive immune system with unrelated pathogens, and to training of the innate immune system through epigenetic reprogramming. Hence, epidemiological findings are backed by immunological data. This generates a new understanding of the immune system and about how it can be modulated by vaccines to impact the general resistance to disease.

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The innate immune response during liver inflammation and metabolic disease.

Publication Date: 2013 May 10 PMID: 23668977
Authors: Bieghs, V. - Trautwein, C.
Journal: Trends Immunol

The role of the inflammatory response is to combat tissue injury and infection. Innate immune cells recognize cell damage or pathogen invasion with intracellular or surface-expressed pattern recognition receptors (PRRs). Activated PRRs subsequently initiate signaling cascades that trigger the release of factors promoting the inflammatory response. Because the liver is a site where foreign antigens from the gastrointestinal tract encounter the immune system, it is particularly enriched with innate immune cells. These cells can modify and disrupt critical processes implicated in metabolic disease. As such, metabolic stress initiates a feedforward cycle of inflammatory responses, resulting in a state of unresolved chronic inflammation in the liver. Accordingly, the crosstalk between these innate immune cells and the resident parenchymal cells plays an important role in the development of acute and chronic liver disease.

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Living and dying for inflammation: neutrophils, eosinophils, basophils.

Publication Date: 2013 May 9 PMID: 23665135
Authors: Geering, B. - Stoeckle, C. - Conus, S. - Simon, H. U.
Journal: Trends Immunol

Neutrophils, eosinophils, and basophils play essential roles during microbe-induced and sterile inflammation. The severity of such inflammatory processes is controlled, at least in part, by factors that regulate cell death and survival of granulocytes. In recent years, major progress has been made in understanding the molecular mechanisms of granulocyte cell death and in identifying novel damage- and pathogen-associated molecular patterns as well as regulatory cytokines impacting granulocyte viability. Furthermore, an increased interest in innate immunity has boosted our overall understanding of granulocyte biology. In this review, we describe and compare factors and mechanisms regulating neutrophil, eosinophil, and basophil lifespan. Because dysregulation of death pathways in granulocytes can contribute to inflammation-associated immunopathology, targeting granulocyte lifespan could be therapeutically promising.

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Cell type-specific function of TAK1 in innate immune signaling.

Publication Date: 2013 May 7 PMID: 23664135
Authors: Ajibade, A. A. - Wang, H. Y. - Wang, R. F.
Journal: Trends Immunol

Transforming growth factor beta-activated kinase 1 (TAK1 or MAP3K7) is a key signaling component of nuclear factor-kappaB (NF-kappaB) and mitogen-activated protein kinase (MAPK) signaling pathways. Activation of TAK1 is tightly regulated through its binding partners and protein modifications. Although TAK1 functions as an essential and positive regulator of innate immune signaling and apoptosis in mouse embryonic fibroblasts (MEFs), T cells, and other cells, it negatively regulates cell development and activation of proinflammatory signaling pathways in neutrophils. However, the molecular mechanisms responsible for the opposite roles of TAK1 in different cell types remain to be addressed. In this article, we discuss the latest progresses in our understanding of TAK1 regulation, function, and mechanisms in a cell-type specific manner.

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MyD88 and its divergent toll in carcinogenesis.

Publication Date: 2013 May 6 PMID: 23660392
Authors: Salcedo, R. - Cataisson, C. - Hasan, U. - Yuspa, S. H. - Trinchieri, G.
Journal: Trends Immunol

Toll-like and interleukin-1 (IL-1) family receptors recognize microbial or endogenous ligands and inflammatory mediators, respectively, and with the exception of Toll-like receptor 3 (TLR3), signal via the adaptor molecule myeloid differentiation factor 88 (MyD88). MyD88 is involved in oncogene-induced cell intrinsic inflammation and in cancer-associated extrinsic inflammation, and as such MyD88 contributes to skin, liver, pancreatic, and colon carcinogenesis, as well as sarcomagenesis. MyD88 is also protective, for example in oncogenic virus carcinogenesis or, acting downstream of IL-18R to strengthen mucosal repair, in azoxymethane (AOM)/dextran sulfate sodium (DSS)-induced colon carcinogenesis. Here, we discuss the mechanisms of the divergent effects of MyD88 and the balance of its protumor role in cancer-enhancing inflammation and immunity and its antitumor role in tissue homeostasis, repair, and immunity against the tumor or oncogenic pathogens.

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Food allergy: an enigmatic epidemic.

Publication Date: 2013 May 3 PMID: 23648309
Authors: Berin, M. C. - Sampson, H. A.
Journal: Trends Immunol

Food allergy is a common disease that is rapidly increasing in prevalence for reasons that remain unknown. Current research efforts are focused on understanding the immune basis of food allergy, identifying environmental factors that may contribute to its rising prevalence, and developing immunotherapeutic approaches to establish immune tolerance to foods. Technological advances such as peptide microarray and MHC class II tetramers have begun to provide a comprehensive profile of the immune response to foods. The burgeoning field of mucosal immunology has provided intriguing clues to the role of the diet and the microbiota as risk factors in the development of food allergy. The purpose of this review is to highlight significant gaps in our knowledge that need answers to stem the progression of this disorder that is reaching epidemic proportions.

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Epigenetics of the antibody response.

Publication Date: 2013 May 2 PMID: 23643790
Authors: Li, G. - Zan, H. - Xu, Z. - Casali, P.
Journal: Trends Immunol

Epigenetic marks, such as DNA methylation, histone post-translational modifications and miRNAs, are induced in B cells by the same stimuli that drive the antibody response. They play major roles in regulating somatic hypermutation (SHM), class switch DNA recombination (CSR), and differentiation to plasma cells or long-lived memory B cells. Histone modifications target the CSR and, possibly, SHM machinery to the immunoglobulin locus; they together with DNA methylation and miRNAs modulate the expression of critical elements of that machinery, such as activation-induced cytidine deaminase (AID), as well as factors central to plasma cell differentiation, such as B lymphocyte-induced maturation protein-1 (Blimp-1). These inducible B cell-intrinsic epigenetic marks instruct the maturation of antibody responses. Their dysregulation plays an important role in aberrant antibody responses to foreign antigens, such as those of microbial pathogens, and self-antigens, such as those targeted in autoimmunity, and B cell neoplasia.

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Effector and memory T cell responses to commensal bacteria.

Publication Date: 2013 May 1 PMID: 23643444
Authors: Belkaid, Y. - Bouladoux, N. - Hand, T. W.
Journal: Trends Immunol

Barrier surfaces are home to a vast population of commensal organisms that together encode millions of proteins; each of them possessing several potential foreign antigens. Regulation of immune responses to this enormous antigenic load represents a tremendous challenge for the immune system. Tissues exposed to commensals have developed elaborate systems of regulation including specialized populations of resident lymphocytes that maintain barrier function and limit potential responses to commensal antigens. However, in settings of infection and inflammation these regulatory mechanisms are compromised and specific effector responses against commensal bacteria can develop. This review discusses the circumstances controlling the fate of commensal specific T cells and how dysregulation of these responses could lead to severe pathological outcomes.

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From genetics of inflammatory bowel disease towards mechanistic insights.

Publication Date: 2013 Apr 29 PMID: 23639549
Authors: Graham, D. B. - Xavier, R. J.
Journal: Trends Immunol

Advancements in human genetics now poise the field to illuminate the pathophysiology of complex genetic disease. In particular, genome-wide association studies (GWAS) have generated insights into the mechanisms driving inflammatory bowel disease (IBD) and implicated genes shared by multiple autoimmune and autoinflammatory diseases. Thus, emerging evidence suggests a central role for the mucosal immune system in mediating immune homeostasis and highlights the complexity of genetic and environmental interactions that collectively modulate the risk of disease. Nevertheless, the challenge remains to determine how genetic variation can precipitate and sustain the inappropriate inflammatory response to commensals that is observed in IBD. Here, we highlight recent advancements in immunogenetics and provide a forward-looking view of the innovations that will deliver mechanistic insights from human genetics.

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Immunological Genome Project and systems immunology.

Publication Date: 2013 Apr 27 PMID: 23631936
Authors: Shay, T. - Kang, J.
Journal: Trends Immunol

Immunological studies of single proteins in a single cell type have been complemented in recent years by larger studies, enabled by emerging high-throughput technologies. This trend has recently been exemplified by the discovery of gene networks controlling regulatory and effector alphabeta T cell subset development and human hematopoiesis. The Immunological Genome Project (ImmGen) aims to decipher the gene networks underpinning mouse hematopoiesis. The first phase, completed in 2012, profiled the transcriptome of 249 immune cell types. We discuss the utilities of the datasets in high-resolution mapping of the hematopoietic system. The immune transcriptome compendium has revealed unsuspected cell lineage relations and the network reconstruction has identified novel regulatory factors of hematopoiesis.

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Regulation of intestinal homeostasis and immunity with probiotic lactobacilli.

Publication Date: 2013 May PMID: 23485516
Authors: van Baarlen, P. - Wells, J. M. - Kleerebezem, M.
Journal: Trends Immunol

The gut microbiota provide important stimuli to the human innate and adaptive immune system and co-mediate metabolic and immune homeostasis. Probiotic bacteria can be regarded as part of the natural human microbiota, and have been associated with improving homeostasis, albeit with different levels of success. Composition of microbiota, probiotic strain identity, and host genetic differences may account for differential modulation of immune responses by probiotics. Here, we review the mechanisms of immunomodulating capacities of specific probiotic strains, the responses they can induce in the host, and how microbiota and genetic differences between individuals may co-influence host responses and immune homeostasis.

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In and out of the bull's eye: protein kinase Cs in the immunological synapse.

Publication Date: 2013 May PMID: 23428395
Authors: Kong, K. F. - Altman, A.
Journal: Trends Immunol

The immunological synapse (IS) formed between immune cells and antigen-presenting cells (APCs) provides a platform for signaling. Protein kinase C (PKC)theta localizes in the T cell IS within the central supramolecular activation cluster (cSMAC), where it associates with CD28 and mediates T cell receptor (TCR)/CD28 signals leading to effector T (Teff) cell activation. In regulatory T (Treg) cells, PKCtheta is sequestered away from the IS, and inhibits suppressive function. Other PKCs localizing in the IS mediate additional functions in various immune cells. Further work is needed to identify mechanisms underlying PKC recruitment or exclusion at the IS, potential redundancy among IS-localized PKCs, and the relevance of PKC localization for IS dynamics and lymphocyte activation.

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T follicular helper cell diversity and plasticity.

Publication Date: 2013 May PMID: 23395212
Authors: Cannons, J. L. - Lu, K. T. - Schwartzberg, P. L.
Journal: Trends Immunol

CD4(+) T helper (Th) cells play an instrumental role in orchestrating adaptive immune responses to invading pathogens through their ability to differentiate into specialized effector subsets. Part of this customized response requires the development of T follicular helper (Tfh) cells, which provide help to B cells for the generation of germinal centers (GCs) and long-term protective humoral responses. Although initially viewed as terminally differentiated, we now recognize that Th cell subsets, including Tfh cells, display substantial flexibility and overlap in their characteristics. In this review, we highlight advances in our understanding of Tfh cell development, cytokine production, and the potential plasticity that allows Tfh cells to possess characteristics of other effector Th cell populations.

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Beyond pattern recognition: NOD-like receptors in dendritic cells.

Publication Date: 2013 May PMID: 23352728
Authors: Krishnaswamy, J. K. - Chu, T. - Eisenbarth, S. C.
Journal: Trends Immunol

Innate instruction of adaptive immunity was proposed more than 20 years ago as a mechanism by which long-lived lymphocyte responses are targeted to appropriate antigens. At the time Charles Janeway proposed this theory, most of the innate immune receptors were unknown, and the pivotal role of the dendritic cell in instructing T cell priming was debated. There is now overwhelming evidence that the innate and adaptive branches of the immune system must interact to generate immunity. Much of this work has focused on families of innate immune receptors called pattern recognition receptors (PRRs) on dendritic cells, which translate these inflammatory triggers into productive T cell responses. Nevertheless, we are only beginning to understand how these defence molecules shape the generation of immunity. We review the varied roles of one class of PRRs, the NOD-like receptors (NLRs), in immune responses and propose a new model in which adaptive immunity requires coordinated PRR activation within the dendritic cell.

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The risks of targeting co-inhibitory pathways to modulate pathogen-directed T cell responses.

Publication Date: 2013 May PMID: 23333205
Authors: Frebel, H. - Oxenius, A.
Journal: Trends Immunol

The identification of T cell co-inhibition as a central mechanism in the regulation of adaptive immunity during infectious diseases provides new opportunities for immunotherapeutic interventions. However, the fact that T cell activity is frequently downregulated during pathogen-directed responses suggests a pivotal physiological role of co-inhibitory pathways during infectious disease. Reports of exacerbated immunopathology in conditions of impaired co-inhibition foster the view that downregulation of T cell activity is an essential negative feedback mechanism that protects from excessive pathogen-directed immunity. Thus, targeting co-inhibitory pathways can bear detrimental potential through the deregulation of physiological processes. Here, we summarize recent preclinical and clinical interventions that report immune-related adverse events after targeting co-inhibitory pathways.

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Epigenetic regulation of macrophage polarization and function.

Publication Date: 2013 May PMID: 23218730
Authors: Ivashkiv, L. B.
Journal: Trends Immunol

Macrophage polarization refers to development of a specific phenotype important for tissue homeostasis or host defense in response to environmental cues. Environmental factors that induce macrophage polarization include cytokines and microbial factors produced by pathogens or commensal microbiota. Signaling pathways utilized by these polarizing factors have been well characterized, but it is less clear how signals are converted into complex and sustained patterns of gene expression, and how macrophages are reprogrammed during polarization to alter their responses to subsequent environmental challenges. Emerging evidence, reviewed here, suggests an important role for epigenetic mechanisms in modulating and transmitting signals during macrophage polarization and reprogramming. Deeper understanding of epigenetic regulation of macrophage phenotype will enable development of gene-specific therapeutic approaches to enhance host defense while preserving tissue integrity and preventing chronic inflammatory diseases.

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