Dynamic regulation of T_h17 differentiation by oxygen concentrations

Naive CD4⁺ T cells are activated by antigen-presenting cells (APCs) and differentiate into distinct types of helper T (T_h) 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 T_h cells remains unclear. Here, we established a novel model of T_h-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 T_h17 cells, but not T_h1 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 T_h17 cells. The activation of mTORC1 and the acceleration of T_h17-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 T_h17-cell differentiation.