Journal
IMMUNITY
Volume 41, Issue 5, Pages 802-814Publisher
CELL PRESS
DOI: 10.1016/j.immuni.2014.10.013
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Funding
- NIH [R37AI066232, R01AI074699, R01AI102888, F32AI096718, T325T32AI007019, F32AI094791, 1-S10-RR-026526-01]
- Howard Hughes Medical Institute
- Australian NHMRC Overseas Biomedical Postdoctoral Fellowship
- Yale Trudeau Fellowship
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Protein kinase B (also known as AKT) and the mechanistic target of rapamycin (mTOR) are central regulators of T cell differentiation, proliferation, metabolism, and survival. Here, we show that during chronic murine lymphocytic choriomeningitis virus infection, activation of AKT and mTOR are impaired in antiviral cytotoxic T lymphocytes (CTLs), resulting in enhanced activity of the transcription factor FoxO1. Blockade of inhibitory receptor programmed cell death protein 1 (PD-1) in vivo increased mTOR activity in virus-specific CTLs, and its therapeutic effects were abrogated by the mTOR inhibitor rapamycin. FoxO1 functioned as a transcriptional activator of PD-1 that promoted the differentiation of terminally exhausted CTLs. Importantly, FoxO1-null CTLs failed to persist and control chronic viral infection. Collectively, this study shows that CTLs adapt to persistent infection through a positive feedback pathway (PD-1-->FoxO1-->PD-1) that functions to both desensitize virus-specific CTLs to antigen and support their survival during chronic viral infection.
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