Hypoxia-inducible factors enhance the effector responses of CD8+ T cells to persistent antigen

被引：559

作者：

Doedens, Andrew L. ^{[1
]}

Phan, Anthony T. ^{[1
]}

Stradner, Martin H. ^{[1
,2
]}

Fujimoto, Jessica K. ^{[1
]}

Nguyen, Jessica V. ^{[1
]}

Yang, Edward ^{[1
]}

Johnson, Randall S. ^{[3
]}

Goldrath, Ananda W. ^{[1
]}

机构：

[1] Univ Calif San Diego, Div Biol Sci, Mol Biol Sect, La Jolla, CA 92093 USA

[2] Med Univ Graz, Div Rheumatol & Immunol, Graz, Austria

[3] Univ Cambridge, Dept Physiol Dev & Neurosci, Cambridge, England

来源：

NATURE IMMUNOLOGY | 2013年 / 14卷 / 11期

基金：

美国国家卫生研究院; 英国惠康基金; 奥地利科学基金会;

关键词：

CHRONIC VIRAL-INFECTION; CHUVASH POLYCYTHEMIA; SELECTIVE EXPRESSION; TUMOR-SUPPRESSOR; EXHAUSTION; DISEASE; GENE; INFLAMMATION; CANCER; MEMORY;

D O I：

10.1038/ni.2714

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

071005 [微生物学]; 100108 [医学免疫学];

摘要：

Cytolytic activity by CD8(+) cytotoxic T lymphocytes (CTLs) is a powerful strategy for the elimination of intracellular pathogens and tumor cells. The destructive capacity of CTLs is progressively dampened during chronic infection, yet the environmental cues and molecular pathways that influence immunological 'exhaustion' remain unclear. Here we found that CTL immunity was regulated by the central transcriptional response to hypoxia, which is controlled in part by hypoxia-inducible factors (HIFs) and the von Hippel-Lindau tumor suppressor VHL. Loss of VHL, the main negative regulator of HIFs, led to lethal CTL-mediated immunopathology during chronic infection, and VHL-deficient CTLs displayed enhanced control of persistent viral infection and neoplastic growth. We found that HIFs and oxygen influenced the expression of pivotal transcription, effector and costimulatory-inhibitory molecules of CTLs, which was relevant to strategies that promote the clearance of viruses and tumors.

引用

页码：1173 / U99

页数：11

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