Dendritic cell SIRT1–HIF1a axis programs the differentiation of CD4+ T cells through IL-12 and TGF-ß1

Liu G1, Bi Y2, Xue L3, Zhang Y4, Yang H4, Chen X4, Lu Y4, Zhang Z4, Liu H4, Wang X4, Wang R5, Chu Y4, Yang R2.
Source: Proc Natl Acad Sci USA
Publication Date: (2015)
Issue: 112(9): E957-65
Research Area:
Immunotherapy / Hematology
Stem Cells
Basic Research
Cells used in publication:
Dendritic cell (NHDC), human
Species: human
Tissue Origin: blood
CD4+, human
Species: human
Tissue Origin: blood
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 (TH1) 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 TH1 development, resulting in an enhanced T-cell-mediated inflammation against microbial responses. Beyond this finding, SIRT1 signaled through a hypoxia-inducible factor-1 alpha (HIF1a)-dependent pathway, orchestrating the reciprocal TH1 and T(reg) lineage commitment through DC-derived IL-12 and TGF-ß1. Our studies implicates a DC-based SIRT1-HIF1a metabolic checkpoint in controlling T-cell lineage specification.