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 T cells 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 T cell fate determination and suggest that metabolic modulation could ameliorate certain T cell-based immune pathologies.
Pubmed ID: 21871655 RIS Download
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Organization which manufactures bacteria for research and clinical investigations. List Biological Laboratories cultivates native and recombinant microorganisms and purifies, formulates, and lyopholizes enzyme products, virulence factors, and microbial cell wall components. Products include antibodies, microbial toxins, peptides, and virulence factors. Services include live biotherapeutics for clinical trials, contracting research capabilities, GMP regulatory support, lyopholization services and support, and toxin compliance.
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