Chronic virus infection enforces demethylation of the locus that encodes PD-1 in antigen-specific CD8(+) T cells.
Chronic virus infection enforces demethylation of the locus that encodes PD-1 in antigen-specific CD8(+) T cells.
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DOI：
10.1016/j.immuni.2011.06.015
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发表时间：
2011-09-23
期刊：
影响因子：
32.4
通讯作者：
Ahmed R
中科院分区：
文献类型：
--
作者：
Youngblood B;Oestreich KJ;Ha SJ;Duraiswamy J;Akondy RS;West EE;Wei Z;Lu P;Austin JW;Riley JL;Boss JM;Ahmed R
功能衰竭的T细胞表达高水平的PD-1抑制受体，阻断PD-1信号传导的治疗有望解决慢性病毒感染和癌症。利用人类和小鼠的急性和慢性病毒感染系统，我们分析了CD8 T细胞分化过程中PD-1表达的表观遗传调控。在急性感染期间，naïve向效应CD8 T细胞分化伴随着Pdcd1位点DNA甲基化的短暂缺失，这与TCR信号传导的持续时间和强度直接相关。进一步分化为功能记忆细胞与Pdcd1再甲基化相吻合，为调节PD-1的表达提供了一个适应的程序。相比之下，在耗尽的CD8 T细胞中，Pdcd1调控区完全去甲基化，即使病毒滴度降低也保持未甲基化。这种DNA再甲基化的缺乏使得Pdcd1基因座处于快速表达的状态，可能为抗病毒功能的过早终止提供信号。
Functionally exhausted T cells express high levels of the PD-1 inhibitory receptor, and therapies that block PD-1 signaling show promise for resolving chronic viral infections and cancer. 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, naïve 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 TCR 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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DOI：
10.1084/jem.20001021
发表时间：
2002-03-04
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Blattman JN;Antia R;Sourdive DJ;Wang X;Kaech SM;Murali-Krishna K;Altman JD;Ahmed R
通讯作者：
Ahmed R
影响因子：
64.5
作者：
Kaech, SM;Hemby, S;Ahmed, R
通讯作者：
Ahmed, R
影响因子：
30.5
作者：
Kaech, SM;Tan, JT;Ahmed, R
通讯作者：
Ahmed, R
影响因子：
15
作者：
Johnson, TB;Coghill, RD
通讯作者：
Coghill, RD
影响因子：
4.4
作者：
Kersh, Ellen N.;Fitzpatrick, David R.;Ahmed, Rafi
通讯作者：
Ahmed, Rafi