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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.

Control of T Cell Fates and Immune Tolerance by p38α Signaling in Mucosal CD103+ Dendritic Cells