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      Regulation of the Immune Response by TGF-β: From Conception to Autoimmunity and Infection

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          Abstract

          Transforming growth factor β (TGF-β) is a pleiotropic cytokine involved in both suppressive and inflammatory immune responses. After 30 years of intense study, we have only begun to elucidate how TGF-β alters immunity under various conditions. Under steady-state conditions, TGF-β regulates thymic T-cell selection and maintains homeostasis of the naïve T-cell pool. TGF-β inhibits cytotoxic T lymphocyte (CTL), Th1-, and Th2-cell differentiation while promoting peripheral (p)Treg-, Th17-, Th9-, and Tfh-cell generation, and T-cell tissue residence in response to immune challenges. Similarly, TGF-β controls the proliferation, survival, activation, and differentiation of B cells, as well as the development and functions of innate cells, including natural killer (NK) cells, macrophages, dendritic cells, and granulocytes. Collectively, TGF-β plays a pivotal role in maintaining peripheral tolerance against self- and innocuous antigens, such as food, commensal bacteria, and fetal alloantigens, and in controlling immune responses to pathogens.

          Abstract

          TGF-β regulates the differentiation and function of different classes of leukocytes, controls the magnitude and type of immune responses against microbes, and helps maintain tolerance against self and benign antigens.

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          Most cited references261

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          TGFbeta in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells.

          We describe de novo generation of IL-17-producing T cells from naive CD4 T cells, induced in cocultures of naive CD4 T cells and naturally occurring CD4+ CD25+ T cells (Treg) in the presence of TLR3, TLR4, or TLR9 stimuli. Treg can be substituted by TGFbeta1, which, together with the proinflammatory cytokine IL-6, supports the differentiation of IL-17-producing T cells, a process that is amplified by IL-1beta and TNFalpha. We could not detect a role for IL-23 in the differentiation of IL-17-producing T cells but confirmed its importance for their survival and expansion. Transcription factors GATA-3 and T-bet, as well as its target Hlx, are absent in IL-17-producing T cells, and they do not express the negative regulator for TGFbeta signaling, Smad7. Our data indicate that, in the presence of IL-6, TGFbeta1 subverts Th1 and Th2 differentiation for the generation of IL-17-producing T cells.
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            Transforming growth factor-beta regulation of immune responses.

            Transforming growth factor-beta (TGF-beta) is a potent regulatory cytokine with diverse effects on hemopoietic cells. The pivotal function of TGF-beta in the immune system is to maintain tolerance via the regulation of lymphocyte proliferation, differentiation, and survival. In addition, TGF-beta controls the initiation and resolution of inflammatory responses through the regulation of chemotaxis, activation, and survival of lymphocytes, natural killer cells, dendritic cells, macrophages, mast cells, and granulocytes. The regulatory activity of TGF-beta is modulated by the cell differentiation state and by the presence of inflammatory cytokines and costimulatory molecules. Collectively, TGF-beta inhibits the development of immunopathology to self or nonharmful antigens without compromising immune responses to pathogens. This review highlights the findings that have advanced our understanding of TGF-beta in the immune system and in disease.
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              IDO expression by dendritic cells: tolerance and tryptophan catabolism.

              Indoleamine 2,3-dioxygenase (IDO) is an enzyme that degrades the essential amino acid tryptophan. The concept that cells expressing IDO can suppress T-cell responses and promote tolerance is a relatively new paradigm in immunology. Considerable evidence now supports this hypothesis, including studies of mammalian pregnancy, tumour resistance, chronic infections and autoimmune diseases. In this review, we summarize key recent developments and propose a unifying model for the role of IDO in tolerance induction.
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                Author and article information

                Journal
                Cold Spring Harb Perspect Biol
                Cold Spring Harb Perspect Biol
                cshperspect
                cshperspect
                Cold Spring Harbor Perspectives in Biology
                Cold Spring Harbor Laboratory Press (Cold Spring Harbor, New York )
                1943-0264
                June 2017
                : 9
                : 6
                : a022236
                Affiliations
                [1 ]Institute of Virology and Immunology, Gladstone Institutes, San Francisco, California 94158
                [2 ]Department of Microbiology and Immunology, University of California, San Francisco, California 94143
                [3 ]Immunology Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065
                Author notes
                [4]

                These authors contributed equally to this work.

                Article
                PMC5453394 PMC5453394 5453394 a022236
                10.1101/cshperspect.a022236
                5453394
                28108486
                9eec6469-7d34-417f-adee-d05ce641c701
                Copyright © 2017 Cold Spring Harbor Laboratory Press; all rights reserved
                History
                Page count
                Pages: 33
                Categories
                088
                Perspectives
                Immunology

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