Dendritic cell SIRT1-HIF1 alpha axis programs the differentiation of CD4+ T cells through IL-12 and TGF- beta 1

The differentiation of naive CD4+ T cells into distinct lineages plays critical roles in mediating adaptive immunity or maintaining immune tolerance. In addition to being a first line of defense, the innate immune system also actively instructs adaptive immunity through antigen presentation and immunoregulatory cytokine production. Here we found that sirtuin 1 (SIRT1), a type III histone deacetylase, plays an essential role in mediating proinflammatory signaling in dendritic cells (DCs), consequentially modulating the balance of proinflammatory T helper type 1 (T...1) cells and antiinflammatory Foxp3+ regulatory T cells (T... cells). Genetic deletion of SIRT1 in DCs restrained the generation of T... cells while driving T...1 development, resulting in an enhanced T-cell-mediated inflammation against microbial responses. Beyond this finding, SIRT1 signaled through a hypoxia-inducible factor-1 alpha (HIF1 alpha )-dependent pathway, orchestrating the reciprocal T...1 and T... lineage commitment through DC-derived IL-12 and TGF- beta 1. Our studies implicates a DC-based SIRT1-HIF1 alpha metabolic checkpoint in controlling T-cell lineage specification. (ProQuest: ... denotes formulae/symbols omitted.)