Dynamic regulation of Th17 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 (O-2) tension is generally low in these secondary lymphoid tissues compared with the bloodstream or atmosphere. However, the effect of changes in O-2 concentration on the differentiation of T-h cells remains unclear. Here, we established a novel model of T-h-cell differentiation, which mimics physiological O-2 conditions. We primed naive CD4(+) T cells under 5% O-2, which has been observed in the lymph node or spleen and reoxygenated under normoxia that mimicked the O-2 concentration in blood. In this model, the differentiation of T(h)17 cells, but not T(h)1 or iTreg cells, was enhanced. Under the condition of 5% O-2, mammalian target of rapamycin complex 1 (mTORC1) was activated and led to the stabilization of hypoxia-inducible factor 1 alpha (HIF-1 alpha) in T(h)17 cells. The activation of mTORC1 and the acceleration of T(h)17-cell differentiation, which occurred when cells were primed under 5% O-2, were not observed in the absence of HIF-1 alpha but were accelerated in the absence of von Hippel-Lindau tumor suppressor protein (vHL), a factor critical for HIF-1 alpha degradation. Thus, a positive feedback loop between HIF-1 alpha and mTORC1 induced by hypoxia followed by reoxygenation accelerates T(h)17-cell differentiation.