Glutaminolysis and mTOR-C/EBPβ 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 Dect-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 being a factor that exerts canonical and epigenetic transcriptional function at separate IL-10 promoter sites. The second involves TGFβ superfamily signaling associated with induction of glutaminolysis and generation of alpha-ketoglutarate, a factor that induces rapamycin-sensitive TORC1 activation; in turn, such activation causes the translation of the LIP isoform of C/EBPβ and the formation of a CREB1-LIP complex that binds to adjacent sites on the IL-10 promoter to facilitate the transactivation of the IL10 gene. Dect-10 T cell regulatory function is manifested through 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.