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Youngblood, Ben,Oestreich, Kenneth ,J.,Ha, Sang-Jun,Duraiswamy, Jaikumar,Akondy, Rama ,S.,West, Erin ,E.,Wei, Zhengyu,Lu, Peiyuan,Austin, James ,W.,Riley, James ,L.,Boss, Jeremy&nb Elsevier 2011 Immunity Vol.35 No.3
<P><B>Summary</B></P><P>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<SUP>+</SUP> T cell differentiation. During acute infection, naive to effector CD8<SUP>+</SUP> T cell differentiation was accompanied by a transient loss of DNA methylation of the <I>Pdcd1</I> locus that was directly coupled to the duration and strength of T cell receptor signaling. Further differentiation into functional memory cells coincided with <I>Pdcd1</I> remethylation, providing an adapted program for regulation of PD-1 expression. In contrast, the <I>Pdcd1</I> regulatory region was completely demethylated in exhausted CD8<SUP>+</SUP> T cells and remained unmethylated even when virus titers decreased. This lack of DNA remethylation leaves the <I>Pdcd1</I> locus poised for rapid expression, potentially providing a signal for premature termination of antiviral functions.</P> <P><B>Highlights</B></P><P>► <I>Pdcd1</I> locus demethylation is coupled to naive to effector CD8<SUP>+</SUP> T cell differentiation ► After <I>Pdcd1</I> remethylation, select CpGs remain unmethylated in memory CD8<SUP>+</SUP> T cells ► Exhausted virus-specific CD8<SUP>+</SUP> T cells retain an unmethylated <I>Pdcd1</I> regulatory region ► Human CD8<SUP>+</SUP> T cells specific to chronic viruses retain an unmethylated <I>PDCD1</I> locus</P>