期刊
IMMUNITY
卷 35, 期 3, 页码 400-412出版社
CELL PRESS
DOI: 10.1016/j.immuni.2011.06.015
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资金
- National Institutes of Health (NIH) [1 P01 AI080192-01, 2 R37 AI30048-17, AHMED05GCGH0]
- American Cancer Society (ACS) [PF-09-134-01-MPC]
- Korea Research Foundation (KRF)
- Korea government (MEST) [2010-0004892]
- National Research Foundation of Korea [2010-0004892] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
Functionally exhausted T cells have high expression of the PD-1 inhibitory receptor, and therapies that block PD-1 signaling show promise for resolving chronic viral infections and cancer. By using human and murine systems of acute and chronic viral infections, we analyzed epigenetic regulation of PD-1 expression during CD8(+) T cell differentiation. During acute infection, naive to effector CD8(+) T cell differentiation was accompanied by a transient loss of DNA methylation of the Pdcd1 locus that was directly coupled to the duration and strength of T cell receptor signaling. Further differentiation into functional memory cells coincided with Pdcd1 remethylation, providing an adapted program for regulation of PD-1 expression. In contrast, the Pdcd1 regulatory region was completely demethylated in exhausted CD8(+) T cells and remained unmethylated even when virus titers decreased. This lack of DNA remethylation leaves the Pdcd1 locus poised for rapid expression, potentially providing a signal for premature termination of antiviral functions.
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