期刊
IMMUNITY
卷 47, 期 6, 页码 1129-+出版社
CELL PRESS
DOI: 10.1016/j.immuni.2017.11.021
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资金
- National Health and Medical Research Council of Australia [1032850, 1085151, 1006592, 1045549, 1065626, 1023454, 1021168, 1116936]
- Walter and Eliza Hall Institute Centenary Fellowship - CSL
- Swiss National Science Foundation
- Novartis Foundation for Medical-Biological Research
- Sylvia and Charles Viertel Foundation
- Fritz Thyssen Stiftung [10.13.2.215]
- Wilhelm Sander-Stiftung [2012.047.1]
- National Health and Medical Research Council of Australia [1116936, 1085151] Funding Source: NHMRC
During chronic stimulation, CD8(+) T cells acquire an exhausted phenotype characterized by expression of inhibitory receptors, down-modulation of effector function, and metabolic impairments. T cell exhaustion protects from excessive immunopathology but limits clearance of virus-infected or tumor cells. We transcriptionally profiled antigen-specific T cells from mice infected with lymphocytic choriomeningitis virus strains that cause acute or chronic disease. T cell exhaustion during chronic infection was driven by high amounts of T cell receptor (TCR)-induced transcription factors IRF4, BATF, and NFATc1. These regulators promoted expression of inhibitory receptors, including PD-1, and mediated impaired cellular metabolism. Furthermore, they repressed the expression of TCF1, a transcription factor required for memory T cell differentiation. Reducing IRF4 expression restored the functional and metabolic properties of antigen-specific T cells and promoted memory-like T cell development. These findings indicate that IRF4 functions as a central node in a TCR-responsive transcriptional circuit that establishes and sustains T cell exhaustion during chronic infection.
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