Negative Regulation of Hif1a Expression and T H 17 Differentiation by Hypoxia Regulated miR-210 Haopeng Wang #1 , Henrik Flach #1 , Michio Onizawa 2 , Lai Wei 3 , Michael T McManus 4 , and Arthur Weiss 1 1 Departments of Medicine and of Microbiology & Immunology, the Rosalind Russell-Ephraim P. Engleman Medical Research Center for Arthritis, and the Howard Hughes Medical Institute, University of California, San Francisco, CA 94143 2 Department of Medicine University of California, San Francisco 3 State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China. 4 Diabetes Center, University of California, San Francisco # These authors contributed equally to this work. Abstract MicroRNA-210 (miR-210) is a signature microRNA of hypoxia. We found robust increase (>100- fold) of miR-210 abundance in activated T cells, especially in the T H 17 lineage. Hypoxia synergized with T cell receptor (TCR)–CD28 stimulation to accelerate and increase the magnitude of Mir210 expression. Mir210 was directly regulated by HIF-1, a key regulator of T H 17 polarization. Surprisingly, Hif1a was identified as a miR-210-target, suggesting negative-feedback by miR-210 to inhibit HIF-1 protein expression. Deletion of Mir210 promoted T H 17 differentiation under conditions with limited oxygen. In experimental colitis, miR-210 reduced Hif1a transcript abundance, reduced the proportion of cells producing inflammatory cytokines and controlled disease severity. Our study identifies miR-210 as an important regulator of T cell differentiation in hypoxia, which can limit immunopathology. Introduction We usually study in vitro T cell responses at the atmospheric O 2 concentration of 21%. However, oxygen tensions in lymphoid tissues are markedly lower (<5%) than those found in peripheral arterial blood (13%) 1, 2 . Immune cells are exposed to varying oxygen tensions in lymphoid organs 2 . T cells are activated during antigen recognition at inflammatory or Correspondence should be addressed to A. W. (aweiss@medicine.ucsf.edu). AUTHOR CONTRIBUTIONS H.W. and H.F. planned and conducted experiments, analyzed and interpreted data and wrote the manuscript. M.O. performed histology analysis. L.W. contributed critical pre-publication data. M.T.M. provided guidance and direction and the Mir210 targeted mice. A.W. supervised the work, helped conceive the experiments, and edited the manuscript. COMPETING INTERESTS STATEMENT The authors declare that they have no competing financial interests. Published as: Nat Immunol. 2014 April ; 15(4): 393–401. HHMI Author Manuscript HHMI Author Manuscript HHMI Author Manuscript