Hypoxia-Inducible Factor Regulates Survival of Antigen Receptor-Driven T Cells

Yuichi Makino, Hiroshi Nakamura, Eiji Ikeda, Kei Ohnuma, Kenji Yamauchi, Yutaka Yabe, Lorenz Poellinger, Yasunori Okada, Chikao Morimoto, Hirotoshi Tanaka

Research output: Contribution to journalArticlepeer-review

115 Citations (Scopus)


Peripheral T lymphocytes undergo activation by antigenic stimulation and function in hypoxic areas of inflammation. We demonstrated in CD3-positive human T cells accumulating in inflammatory tissue expression of the hypoxia-inducible factor-1α (HIF-1α), indicating a role of hypoxia-mediated signals in regulation of T cell function. Surprisingly, accumulation of HIF-1α in human T cells required not only hypoxia but also TCR/CD3-mediated activation. Moreover, hypoxia repressed activation-induced cell death (AICD) by TCR/CD3 stimulation, resulting in an increased survival of the cells. Microarray analysis suggested the involvement of HIF-1 target gene product adrenomedullin (AM) in this process. Indeed, AM receptor antagonist abrogated hypoxia-mediated repression of AICD. Moreover, synthetic AM peptides repressed AICD even in normoxia. Taken together, we propose that hypoxia is a critical determinant of survival of the activated T cells via the HIF-1α-AM cascade, defining a previously unknown mode of regulation of peripheral immunity.

Original languageEnglish
Pages (from-to)6534-6540
Number of pages7
JournalJournal of Immunology
Issue number12
Publication statusPublished - 2003 Dec 15
Externally publishedYes

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology


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