Dendritic cell SIRT1–HIF1α axis programs the differentiation of CD4⁺ T cells through IL-12 and TGF-β1

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 H1) cells and antiinflammatory Foxp3 ⁺ regulatory T cells (T ᵣₑg cells). Genetic deletion of SIRT1 in DCs restrained the generation of T ᵣₑg cells while driving T H1 development, resulting in an enhanced T-cell–mediated inflammation against microbial responses. Beyond this finding, SIRT1 signaled through a hypoxia-inducible factor-1 alpha (HIF1α)-dependent pathway, orchestrating the reciprocal T H1 and T ᵣₑg lineage commitment through DC-derived IL-12 and TGF-β1. Our studies implicates a DC-based SIRT1–HIF1α metabolic checkpoint in controlling T-cell lineage specification. Significance Naive CD4 ⁺ T cells differentiate into diverse effector and regulatory subsets to orchestrate immunity and tolerance. Whereas the mechanism of T-cell intrinsic signals has been extensively studied, how T-cell lineage differentiation is controlled by innate immune signals remains unknown. Here we used loss-of-function mouse systems, combined with other complementary approaches and models, to define the role of dendritic cell (DC) sirtuin 1 (SIRT1) as a key regulator in orchestrating the orientation of T-cell differentiation via HIF1α signaling in a mammalian target of rapamycin–independent manner. DC-expressed SIRT1, a type III histone deacetylase, programmed reciprocal T helper 1 (T H1) and regulatory T-cell (T ᵣₑg) differentiation by modulating IL-12–STAT4 and TGF-β1–SMAD3 axes and cytokine receptor expressions at the DC–T-cell interface.