Dynamic regulation of Th17 differentiation by oxygen concentrations

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Naive CD4+ T cells are activated by antigen-presenting cells (APCs) and differentiate into distinct types of helper T (Th) cells in the lymph node or spleen. Oxygen (O2) tension is generally low in these secondary lymphoid tissues compared with the bloodstream or atmosphere. However, the effect of changes in O2 concentration on the differentiation of Th cells remains unclear. Here, we established a novel model of Th-cell differentiation, which mimics physiological O2 conditions. We primed naive CD4+ T cells under 5% O2, which has been observed in the lymph node or spleen and reoxygenated under normoxia that mimicked the O2 concentration in blood. In this model, the differentiation of Th17 cells, but not Th1 or iTreg cells, was enhanced. Under the condition of 5% O2, mammalian target of rapamycin complex 1 (mTORC1) was activated and led to the stabilization of hypoxia-inducible factor 1α (HIF-1α) in Th17 cells. The activation of mTORC1 and the acceleration of Th17-cell differentiation, which occurred when cells were primed under 5% O2, were not observed in the absence of HIF-1α but were accelerated in the absence of von Hippel–Lindau tumor suppressor protein (vHL), a factor critical for HIF-1α degradation. Thus, a positive feedback loop between HIF-1α and mTORC1 induced by hypoxia followed by reoxygenation accelerates Th17-cell differentiation.

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