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 1α (HIF-1α) 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-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(h)17-cell differentiation.
Department of Microbiology and Immunology, Keio University School of Medicine, Shinjuku-ku, Tokyo 160-8582, Japan.
Ai
A
Ikejiri
Shigenori
S
Nagai
Nobuhito
N
Goda
Yutaka
Y
Kurebayashi
Mayuko
M
Osada-Oka
Keiyo
K
Takubo
Toshio
T
Suda
Shigeo
S
Koyasu
D000818:Animals; D015153:Blotting, Western; D002454:Cell Differentiation / Q000502:physiology*; D015687:Cell Hypoxia / Q000502:physiology; D025461:Feedback, Physiological; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D046912:Multiprotein Complexes; D010100:Oxygen / Q000502:physiology*; D011506:Proteins / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology; D058570:TOR Serine-Threonine Kinases; D058504:Th17 Cells / Q000166:cytology*
C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D046912:Multiprotein Complexes; D011506:Proteins; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D010100:Oxygen