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      TLR2 dependent induction of vitamin A metabolizing enzymes in dendritic cells promotes T regulatory responses and inhibits T H-17 mediated autoimmunity

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          Abstract

          Immune sensing of a microbe occurs via multiple receptors. How signals from different receptors are coordinated to yield a specific immune response is poorly understood. We demonstrate that the different pathogen recognition receptors, TLR2 and dectin-1, recognizing the same microbial stimulus, stimulate distinct innate and adaptive responses. TLR2 signaling induced splenic dendritic cells (DCs) to express the retinoic acid (RA) metabolizing enzyme Raldh2 and IL-10, and to metabolize vitamin A and stimulate Foxp3 + T regulatory cells (Treg cells). RA acted on DCs to induce Socs3 expression, which suppressed activation of p38 MAPK and pro-inflammatory cytokines. Consistent with this, TLR2 signaling induced Treg cells, and suppressed IL-23 and T H-17/ T H-1 mediated autoimmune responses in vivo. In contrast, dectin-1 signaling mostly induced IL-23 and pro-inflammatory cytokines, and augmented T H-17/ T H-1 mediated autoimmune responses in vivo. These data define a new mechanism for the systemic induction of RA and immune suppression against autoimmunity.

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          Most cited references37

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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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            Taking dendritic cells into medicine.

            Dendritic cells (DCs) orchestrate a repertoire of immune responses that bring about resistance to infection and silencing or tolerance to self. In the settings of infection and cancer, microbes and tumours can exploit DCs to evade immunity, but DCs also can generate resistance, a capacity that is readily enhanced with DC-targeted vaccines. During allergy, autoimmunity and transplant rejection, DCs instigate unwanted responses that cause disease, but, again, DCs can be harnessed to silence these conditions with novel therapies. Here we present some medical implications of DC biology that account for illness and provide opportunities for prevention and therapy.
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              Immune recognition. A new receptor for beta-glucans.

              The carbohydrate polymers known as beta-1,3-d-glucans exert potent effects on the immune system - stimulating antitumour and antimicrobial activity, for example - by binding to receptors on macrophages and other white blood cells and activating them. Although beta-glucans are known to bind to receptors, such as complement receptor 3 (ref. 1), there is evidence that another beta-glucan receptor is present on macrophages. Here we identify this unknown receptor as dectin-1 (ref. 2), a finding that provides new insights into the innate immune recognition of beta-glucans.
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                Author and article information

                Journal
                9502015
                8791
                Nat Med
                Nature medicine
                1078-8956
                1546-170X
                28 April 2009
                1 March 2009
                April 2009
                27 October 2009
                : 15
                : 4
                : 401-409
                Affiliations
                [1 ]Emory Vaccine Center, and Yerkes National Primate Research Center, 954 Gatewood Road, Atlanta, GA 30329, USA
                [2 ]Department of Microbiology and Immunology, Emory University, 1510 Clifton Road, Atlanta, GA 30322 USA
                [3 ]Department of Pathology, Emory University, 1364 Clifton Road NE, Atlanta, GA 30322, 30322, USA
                Author notes
                [4 ]Correspondence to: Bali Pulendran, Emory Vaccine Center, 954 Gatewood Road, Atlanta, GA 30329, USA. Email: bpulend@ 123456.emory.edu

                AUTHOR CONTRIBUTIONS

                S.M performed the experiments in the study, prepared the figures and helped write the paper. R.R assisted S.M with some of the experiments. J.D. performed some of the initial experiments. H.O performed the immunohistology analysis. T.L.D provided discussion and advice on some parts of the study. S.P.K encapsulated disulphiram in microparticles. K.M.R and B.D.E assisted with the EAE experiments. B.P conceived and supervised the study, and with S.M, wrote the paper.

                Article
                nihpa103171
                10.1038/nm.1925
                2768543
                19252500
                02e27db7-cef8-4292-a5f7-50b366b62688
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