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Trends in Immunology

Dimitrios C Mastellos, Edimara S Reis, Daniel Ricklin, Richard J Smith, John D Lambris
Complement dysregulation underlies several inflammatory disorders, and terminal complement inhibition has thus far afforded significant clinical gains. Nonetheless, emerging pathologies, fueled by complement imbalance and therapy-skewing genetic variance, underscore the need for more comprehensive, disease-tailored interventions. Modulation at the level of C3, a multifaceted orchestrator of the complement cascade, opens up prospects for broader therapeutic efficacy by targeting multiple pathogenic pathways modulated by C3-triggered proinflammatory crosstalk...
April 14, 2017: Trends in Immunology
Itziar Martinez-Gonzalez, Laura Mathä, Catherine A Steer, Fumio Takei
Immunological memory has long been described as a property of the adaptive immune system that results in potent responses on exposure to an antigen encountered previously. While this definition appears to exclude cells that do not express antigen receptors, recent studies have shown that innate immune cells, including natural killer (NK) cells, macrophages, and, more recently, group 2 innate lymphoid cells (ILC2s) can record previous activations and respond more vigorously on reactivation. Here we review the similarities and differences between these forms of memory and the underlying mechanisms...
April 14, 2017: Trends in Immunology
Shally R Margolis, Stephen C Wilson, Russell E Vance
Detection of foreign nucleic acids is an important strategy for innate immune recognition of pathogens. In vertebrates, pathogen-derived DNA is sensed in the cytosol by cGAS, which produces the cyclic dinucleotide (CDN) second messenger cGAMP to activate the signaling adaptor STING. While induction of antiviral type I interferons (IFNs) is the major outcome of STING activation in vertebrates, it has recently become clear that core components of the cGAS-STING pathway evolved more than 600 million years ago, predating the evolution of type I IFNs...
April 14, 2017: Trends in Immunology
Anne-Marie Pauwels, Matthias Trost, Rudi Beyaert, Eik Hoffmann
Recognition of microbial pathogens and dead cells and their phagocytic uptake by specialized immune cells are essential to maintain host homeostasis. Phagosomes undergo fusion and fission events with endosomal and lysosomal compartments, a process called 'phagosome maturation', which leads to the degradation of the phagosomal content. However, many phagocytic cells also act as antigen-presenting cells and must balance degradation and peptide preservation. Emerging evidence indicates that receptor engagement by phagosomal cargo, as well as inflammatory mediators and cellular activation affect many aspects of phagosome maturation...
April 14, 2017: Trends in Immunology
Jan Van den Bossche, Luke A O'Neill, Deepthi Menon
A growing number of findings highlight the crucial role of metabolic reprogramming in macrophage activation. Metabolic pathways are closely interconnected and recent literature demonstrates the need for glucose metabolism in anti-inflammatory as well as inflammatory macrophages. Moreover, fatty acid oxidation (FAO) not only supports anti-inflammatory responses as described formerly but also drives inflammasome activation in inflammatory macrophages. Hence, defining glycolysis as proinflammatory and FAO as anti-inflammatory may be an oversimplification...
April 7, 2017: Trends in Immunology
Madeleine F Jennewein, Galit Alter
Beyond their role in neutralization, antibodies mediate functions such as phagocytosis, cytotoxicity, and maintenance of immune homeostasis. Two modifications to the constant domain control antibody activity: theirreversible genomic selection of isotype/subclass and alterations in glycosylation. Because glycosylation alters the affinity of antibodies for Fc receptors, evidence suggests that glycosylation is a central mechanism for the immune system to tune a broad range of biological activities. While monoclonal therapeutics have exploited glycosylation to improve function, its in vivo control and whether it may be selectively harnessed to target pathogens and/or tumors isunknown...
April 3, 2017: Trends in Immunology
Victoria Male
Mouse liver contains two natural killer (NK) cell populations, one of which recirculates while the other is tissue resident. Following this discovery, several groups have sought to identify liver-resident NK (lrNK) cells in humans. Here, I present an overview of recent advances in the field.
March 15, 2017: Trends in Immunology
Miguel Muñoz-Ruiz, Nital Sumaria, Daniel J Pennington, Bruno Silva-Santos
γd T cells have emerged as major sources of the proinflammatory cytokines interleukin-17 (IL-17) and interferon-γ (IFNγ) in multiple models of infection, cancer and autoimmune disease. However, unlike their αβ T cell counterparts that require peripheral activation for effector cell differentiation, γδ T cells instead can be 'developmentally programmed' in the thymus to generate discrete γδ T cell effector subsets with distinctive molecular signatures. Nonetheless, recent studies have presented conflicting viewpoints on the signals involved in thymic γδ T cell development and differentiation, namely on the role of both T cell receptor (TCR)-dependent and TCR-independent factors...
March 9, 2017: Trends in Immunology
Henrique Veiga-Fernandes, António A Freitas
Viewpoints on the immune system have evolved across different paradigms, including the clonal selection theory, the idiotypic network, and the danger and tolerance models. Herein, we propose that in multicellular organisms, where panoplies of cells from different germ layers interact and immune cells are constantly generated, the behavior of the immune system is defined by the rules governing cell survival, systems physiology and organismic homeostasis. Initially, these rules were imprinted at the single cell-protist level, but supervened modifications in the transition to multicellular organisms...
March 7, 2017: Trends in Immunology
Peter A Morawski, Silvia Bolland
Systemic lupus erythematosus (SLE) is an autoimmune disorder characterized by a breakdown of self-tolerance in B cells and the production of antibodies against nuclear self-antigens. Increasing evidence supports the notion that additional cellular contributors beyond B cells are important for lupus pathogenesis. In this review we consider recent advances regarding both the pathogenic and the regulatory role of lymphocytes in SLE beyond the production of IgG autoantibodies. We also discuss various inflammatory effector cell types involved in cytokine production, removal of self-antigens, and responses to autoreactive IgE antibodies...
March 5, 2017: Trends in Immunology
Roberto Tinoco, Dennis C Otero, Amy A Takahashi, Linda M Bradley
P-selectin glycoprotein ligand-1 (PSGL-1) has long been studied as an adhesion molecule involved in immune cell trafficking and is recognized as a regulator of many facets of immune responses by myeloid cells. PSGL-1 also regulates T cell migration during homeostasis and inflammatory settings. However, recent findings indicate that PSGL-1 can also negatively regulate T cell function. Because T cell differentiation is finely tuned by multiple positive and negative regulatory signals that appropriately scale the magnitude of the immune response, PSGL-1 has emerged as an important checkpoint during this process...
March 2, 2017: Trends in Immunology
Silvia Bulfone-Paus, Gunnar Nilsson, Petr Draber, Ulrich Blank, Francesca Levi-Schaffer
Mast cells are powerful immune modulators of the tissue microenvironment. Within seconds of activation, these cells release a variety of preformed biologically active products, followed by a wave of mediator synthesis and secretion. Increasing evidence suggests that an intricate network of inhibitory and activating receptors, specific signaling pathways, and adaptor proteins governs mast cell responsiveness to stimuli. Here, we discuss the biological and clinical relevance of negative and positive signaling modalities that control mast cell activation, with an emphasis on novel FcεRI regulators, immunoglobulin E (IgE)-independent pathways [e...
February 18, 2017: Trends in Immunology
Nilesh Amatya, Abhishek V Garg, Sarah L Gaffen
Interleukin (IL)-17 is the founding member of a novel family of inflammatory cytokines. While the proinflammatory properties of IL-17 are key to its host-protective capacity, unrestrained IL-17 signaling is associated with immunopathology, autoimmune disease, and cancer progression. In this review we discuss both the activators and the inhibitors of IL-17 signal transduction, and also the physiological implications of these events. We highlight the surprisingly diverse means by which these regulators control expression of IL-17-dependent inflammatory genes, as well as the major target cells that respond to IL-17 signaling...
February 18, 2017: Trends in Immunology
Steffen Boettcher, Markus G Manz
Innate myeloid immune cells, and neutrophils in particular, serve as first line of defense against pathogenic microorganisms including bacteria and fungi. Given their short life span during steady-state conditions, myeloid cells - with, in some cases, the exception of tissue macrophages - need to be constantly regenerated from hematopoietic stem and progenitor cells. During severe systemic bacterial infection, myeloid cell turnover is dramatically increased due to their unique modus operandi in combating invading pathogens involving release of lytic enzymes and neutrophil extracellular traps...
February 16, 2017: Trends in Immunology
Leonardo M R Ferreira, Torsten B Meissner, Tamara Tilburgs, Jack L Strominger
During pregnancy, semiallogeneic fetal extravillous trophoblasts (EVT) invade the uterine mucosa without being rejected by the maternal immune system. Several mechanisms were initially proposed by Peter Medawar half a century ago to explain this apparent violation of the laws of transplantation. Then, three decades ago, an unusual human leukocyte antigen (HLA) molecule was identified: HLA-G. Uniquely expressed in EVT, HLA-G has since become the center of the present understanding of fetus-induced immune tolerance...
April 2017: Trends in Immunology
Axel Kallies, Kim L Good-Jacobson
T-bet was originally described as the key transcription factor defining type 1 T helper (Th) cells. However, it is now clear that it drives the orchestrated generation of effector and memory cells in multiple different lymphocyte lineages. In addition to Th1 cells, CD8 T cells, B cells and some innate lymphocyte populations require T-bet for their development or differentiation in response to antigen. Furthermore, other Th cell populations, including T follicular helper and Th17, as well as regulatory T cells can co-opt T-bet expression to promote functional diversification and colocalization...
April 2017: Trends in Immunology
Shin-Rong Wu, Pavan Reddy
The severity of immunopathology from non-infectious inflammation is mainly understood and is managed by targeting immune cells. However, the role of target tissues in determining damage severity has been largely overlooked. Here, we discuss the concept of 'tissue tolerance' for tissue-intrinsic programs that ameliorate organ damage in the setting of sterile immunopathology.
April 2017: Trends in Immunology
Chao Zhong, Jinfang Zhu
Although small-molecule thymus-specific isoform of retinoic acid receptor-related orphan nuclear receptor γ (RORγt) antagonists suppressing interleukin (IL)-17-producing T helper (Th17) cells are widely reported, the effect of these molecules on other RORγt-expressing cells is unknown. However, a new study reports that RORγt inhibition in CD4(+)CD8(+) thymocytes resulted in skewed T cell repertoire, contributing to a reduction in the frequency of self-reactive T cells and resistance to autoimmunity.
April 2017: Trends in Immunology
Stephanie C Casey, Virginie Baylot, Dean W Felsher
Cancers are often initiated by genetic events that activate proto-oncogenes or inactivate tumor-suppressor genes. These events are also crucial for sustained tumor cell proliferation and survival, a phenomenon described as oncogene addiction. In addition to this cell-intrinsic role, recent evidence indicates that oncogenes also directly regulate immune responses, leading to immunosuppression. Expression of many oncogenes or loss of tumor suppressors induces the expression of immune checkpoints that regulate the immune response, such as PD-L1...
April 2017: Trends in Immunology
Maayan Levy, Hagit Shapiro, Christoph A Thaiss, Eran Elinav
NLRP6, a member of the nucleotide-binding domain, leucine-rich repeat-containing (NLR) innate immune receptor family, regulates inflammation and host defense against microorganisms. Similar to other NLRs, NLRP6 not only participates in inflammasome formation, but is also involved in nuclear factor-κB (NF-κB) and mitogen-activated protein kinase (MAPK) signaling regulation and facilitation of gastrointestinal antiviral effector functions. Additionally, NLRP6 contributes to the regulation of mucus secretion and antimicrobial peptide production, thereby impacting intestinal microbial colonization and associated microbiome-related infectious, autoinflammatory, metabolic, and neoplastic diseases...
April 2017: Trends in Immunology
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