title: Control of T cell fates and immune tolerance by p38α signaling in mucosal CD103+ dendritic cells.
abstract: Dendritic cells (DCs) play a crucial role in launching protective adaptive immunity against pathogens while maintaining immune tolerance to self-Ags. However, how intracellular signaling pathways program DCs to mediate tolerogenic responses remains largely unexplored. In this study, we describe that p38α signaling in CD103(+) mesenteric lymph node DCs reciprocally regulates the differentiation of anti-inflammatory induced regulatory T cells and proinflammatory Th1 cells from naive precursors and promotes mucosal tolerance. Deficiency of p38α in CD103(+) DCs inhibited the generation of induced regulatory T cells while promoting Th1 cell development in a TGF-β2-dependent manner. Consequently, loss of p38α in DCs prevented induction of oral tolerance in vivo. Moreover, p38α in CD103(+) DCs was required for optimal expression of retinaldehyde dehydrogenase, a key enzyme for retinoic acid synthesis, which in turn imprinted gut-homing receptors on responding T cells. Consistent with a crucial role of p38α to program the tolerogenic activity of CD103(+) DCs, such DC subset contained constitutive activity of p38α and abundant expression of TGF-β2 and retinaldehyde dehydrogenase. Our studies identify a key mechanism of DC-mediated coupling of T cell differentiation and trafficking that orchestrates mucosal immune tolerance.
authors.affiliation: Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Gonghua
authors.initials: G
authors.lastname: Huang
authors.forename: Yanyan
authors.initials: Y
authors.lastname: Wang
authors.forename: Hongbo
authors.initials: H
authors.lastname: Chi
mesh_terms: D056704:Adaptive Immunity; D000080924:Aldehyde Dehydrogenase 1 Family; D000818:Animals; D015703:Antigens, CD / Q000032:analysis*; D002454:Cell Differentiation; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D007108:Immune Tolerance; D039001:Integrin alpha Chains / Q000032:analysis*; D007527:Isoenzymes / Q000096:biosynthesis; D008198:Lymph Nodes / Q000276:immunology; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D048308:Mitogen-Activated Protein Kinase 14 / Q000378:metabolism*; D050697:Retinal Dehydrogenase / Q000096:biosynthesis; D015398:Signal Transduction; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology; D053781:Transforming Growth Factor beta2 / Q000378:metabolism; D014212:Tretinoin / Q000378:metabolism
chemical_list: D015703:Antigens, CD; D039001:Integrin alpha Chains; D007527:Isoenzymes; D053781:Transforming Growth Factor beta2; C091367:alpha E integrins; D014212:Tretinoin; D000080924:Aldehyde Dehydrogenase 1 Family; C515028:ALDH1A1 protein, mouse; D050697:Retinal Dehydrogenase; D048308:Mitogen-Activated Protein Kinase 14