Hypoxia-inducible factor regulates survival of antigen receptor-driven T cells.
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-1alpha (HIF-1alpha), indicating a role of hypoxia-mediated signals in regulation of T cell function. Surprisingly, accumulation of HIF-1alpha 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-1alpha-AM cascade, defining a previously unknown mode of regulation of peripheral immunity.
Makino
Yuichi
Y
Division of Clinical Immunology, Advanced Clinical Research Center, Institute of Medical Science, University of Tokyo, Japan.
Nakamura
Hiroshi
H
Ikeda
Eiji
E
Ohnuma
Kei
K
Yamauchi
Kenji
K
Yabe
Yutaka
Y
Poellinger
Lorenz
L
Okada
Yasunori
Y
Morimoto
Chikao
C
Tanaka
Hirotoshi
H
D053607:Adrenomedullin; D001172:Arthritis, Rheumatoid / Q000276:immunology / Q000473:pathology; D019898:Autocrine Communication / Q000276:immunology; D016923:Cell Death / Q000235:genetics / Q000276:immunology; D015687:Cell Hypoxia / Q000235:genetics / Q000276:immunology; D002470:Cell Survival / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D015536:Down-Regulation / Q000276:immunology; D020869:Gene Expression Profiling; D006801:Humans; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D019169:Jurkat Cells; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology*; D009687:Nuclear Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D020411:Oligonucleotide Array Sequence Analysis; D010455:Peptides / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D017260:Receptor-CD3 Complex, Antigen, T-Cell / Q000502:physiology*; D013583:Synovial Membrane / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D016176:T-Lymphocyte Subsets / Q000166:cytology* / Q000276:immunology / Q000378:metabolism*; D014157:Transcription Factors
D004268:DNA-Binding Proteins; C497442:HIF1A protein, human; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009687:Nuclear Proteins; D010455:Peptides; D017260:Receptor-CD3 Complex, Antigen, T-Cell; D014157:Transcription Factors; D053607:Adrenomedullin