Differential CTLA-4 expression in human CD4+ versus CD8+ T cells is associated with increased NFAT1 and inhibition of CD4+ proliferation.
Differential CTLA-4 expression in human CD4+ versus CD8+ T cells is associated with increased NFAT1 and inhibition of CD4+ proliferation.
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DOI：
10.1038/gene.2013.57
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发表时间：
2014-01
影响因子：
5
通讯作者：
Wong, H. K.
中科院分区：
文献类型：
--
作者：
Chan, D. V.;Gibson, H. M.;Aufiero, B. M.;Wilson, A. J.;Hafner, M. S.;Mi, Q-S;Wong, H. K.
CTLA-4是负调节T细胞活化的共刺激分子。最初在鼠CD 8 + T细胞中鉴定，现已发现其在人T细胞上被快速诱导。此外，CTLA-4在调节性T细胞（Tcells）上表达。在临床上，靶向CTLA-4在治疗黑色素瘤中具有临床效用。CTLA-4的表达是否在CD 8+与CD 4+人T细胞中差异调节尚不清楚。在这里，我们分析了正常人CD 4+和CD 8 + T细胞亚群中的CTLA-4，并首次显示CTLA-4在CD 4 + T细胞中的表达显著高于在CD 8 + T细胞中的表达。CTLA-4在CD 4 + T细胞中在蛋白和转录水平上更高。这种增加是由于CTLA-4启动子的激活，其在近端启动子处经历乙酰化。此外，我们表明，阻断CD 4 + T细胞上的CTLA-4允许CD 4+细胞相对于CD 8+细胞更大的增殖。这些发现证明了CTLA-4对CD 4+和CD 8 + T细胞亚群的差异调节，这可能对抗CTLA-4疗法的临床疗效很重要。这些发现提示了通过靶向表观遗传转录来调节CTLA-4表达以改变免疫应答的策略。
CTLA-4 is a costimulatory molecule that negatively regulates T cell activation. Originally identified in murine CD8+ T cells, it has been found to be rapidly induced on human T cells. Furthermore, CTLA-4 is expressed on regulatory T cells (Tregs). Clinically, targeting CTLA-4 has clinical utility in the treatment of melanoma. Whether the expression of CTLA-4 is differentially regulated in CD8+ vs. CD4+ human T cells is unclear. Here we analyzed CTLA-4 in normal human CD4+ and CD8+ T cell subsets and show for the first time that CTLA-4 is expressed significantly higher in the CD4+ T cells than in CD8+ T cells. CTLA-4 is higher at the protein and the transcriptional level in CD4+ T cells. This increase is due to activation of the CTLA-4 promoter, which undergoes acetylation at the proximal promoter. Furthermore, we show that blocking CTLA-4 on CD4+ T cells permits greater proliferation in CD4+ vs. CD8+ cells. These findings demonstrate a differential regulation of CTLA-4 on CD4+ and CD8+ T cell subsets, which is likely important to the clinical efficacy for anti-CTLA-4 therapies. The findings hint to strategies to modulate CTLA-4 expression by targeting epigenetic transcription to alter the immune response.
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DOI：
10.1056/nejmoa1003466
发表时间：
2010-08-19
期刊：
The New England journal of medicine
影响因子：
--
作者：
Hodi FS;O'Day SJ;McDermott DF;Weber RW;Sosman JA;Haanen JB;Gonzalez R;Robert C;Schadendorf D;Hassel JC;Akerley W;van den Eertwegh AJ;Lutzky J;Lorigan P;Vaubel JM;Linette GP;Hogg D;Ottensmeier CH;Lebbé C;Peschel C;Quirt I;Clark JI;Wolchok JD;Weber JS;Tian J;Yellin MJ;Nichol GM;Hoos A;Urba WJ
通讯作者：
Urba WJ
影响因子：
5.4
作者：
DARIAVACH, P;MATTEI, MG;LEFRANC, MP
通讯作者：
LEFRANC, MP
DOI：
10.1073/pnas.0910341107
发表时间：
2010-01-26
影响因子：
11.1
作者：
Jain, Nitya;Nguyen, Hai;Kang, Joonsoo
通讯作者：
Kang, Joonsoo
DOI：
10.1084/jem.20081811
发表时间：
2009-02-16
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Friedline RH;Brown DS;Nguyen H;Kornfeld H;Lee J;Zhang Y;Appleby M;Der SD;Kang J;Chambers CA
通讯作者：
Chambers CA
影响因子：
64.8
作者：
BRUNET, JF;DENIZOT, F;GOLSTEIN, P
通讯作者：
GOLSTEIN, P