ALK4R–Stimulated Glutaminolysis and mTOR-C/EBPbeta Signaling Drives the Differentiation of Novel IL-10-Producing Regulatory T Cells

Here we report that Dectin-1-stimulated dendritic cells (DCs) induce unique IL-10-producing T cells with strong regulatory function during fungal infection or experimental asthma.These T cells, which we call Dectin-10 T cells, are induced by DC-initiated signaling that sets in motion two complementary mechanisms of IL-10-producing T cell differentiation. The first involves induction of nascent Dect-10 T cell IL-4 synthesis and attendant GATA3 production, the latter a factor that exerts canonical and epigenetic transcriptional function at separate IL-10 promoter sites. The second involves TGFbetaR-family(ActRIB(ALK4)) signaling associated with induction of glutaminolysis and generation of alpha-ketoglutarate, a factor that induces rapamycin-sensitive TORC1 activation; the latter, in turn, causes translation of the LIP isoform of C/EBPbeta and binding LIP to CREB1 to form a CREB1-LIP complex that binds to adjacent sites on the IL- 10 promoter and transactivation of the IL10 gene. Dect-10 T cell regulatory function is manifest by its capacity to down-regulate normally protective immune responses to hyphal C. albicans renal infection. In addition, Dect-10 T cells, in accord with their IL-4-dependent genesis, suppress dust mite-induced experimental asthma.