Control of T(H)17/T(reg) balance by hypoxia-inducible factor 1.
摘要：
T cell differentiation into distinct functional effector and inhibitory subsets is regulated, in part, by the cytokine environment present at the time of antigen recognition. Here, we show that hypoxia-inducible factor 1 (HIF-1), a key metabolic sensor, regulates the balance between regulatory T cell (T reg ) and T H 17 differentiation. HIF-1 enhances T H 17 development through direct transcriptional activation of RORγt and via tertiary complex formation with RORγt and p300 recruitment to the IL-17 promoter, thereby regulating T H 17 signature genes. Concurrently, HIF-1 attenuates T reg development by binding Foxp3 and targeting it for proteasomal degradation. Importantly, this regulation occurs under both normoxic and hypoxic conditions. Mice with HIF-1α-deficient Tcells are resistant to induction of T H 17-dependent experimental autoimmune encephalitis associated with diminished T H 17 and increased T reg cells. These findings highlight the importance of metabolic cues in Tcell fate determination and suggest that metabolic modulation could ameliorate certain Tcell-based immune pathologies.
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关键词：
Jurkat Cells Animals Humans Mice Encephalomyelitis, Autoimmune, Experimental Interleukin-17 Sequence Alignment Base Sequence Molecular Sequence Data T-Lymphocytes, Regulatory
DOI：
10.1016/j.cell.2011.07.033
被引量：
年份：
2011
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