Allelic variant in CTLA4 alters T cell phosphorylation patterns
Allelic variant in CTLA4 alters T cell phosphorylation patterns
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DOI：
10.1073/pnas.0706409104
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发表时间：
2007-11-20
影响因子：
11.1
通讯作者：
Hafler, David A.
中科院分区：
文献类型：
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作者：
Maier, Lisa M.;Anderson, David E.;Hafler, David A.
关于常见的自身免疫易感性变体对人类免疫细胞的功能影响知之甚少。位于CTLA 4基因3' UTR的SNIP CT60（rs3087243; A/G）与自身免疫性疾病相关。我们检查了一组按CTLA 4基因型分层的健康个体，以深入了解等位基因变异对T细胞信号传导的功能影响。使用磷酸化位点特异性单克隆抗体，我们测试了CTLA 4处的CT60基因型与幼稚和/或记忆T细胞中改变的T细胞抗原受体（TCR）信号传导相关的假设。通过对CD 3 zeta处的初始TCR信号事件的程度进行标准化，我们观察到，通过下游信号分子的磷酸化水平评估的对TCR刺激的相对反应性在从CTLA 4处具有疾病易感性等位基因的个体获得的初始（CD 4（+）CD 45 RA（高））和记忆（CD 4（+）CD 45 RA（低））T细胞中发生了改变。因此，与自身免疫性疾病相关的等位基因变异可以改变CD 4（+）T细胞的信号转导阈值。这些实验为解剖自身免疫性疾病的T细胞易感基因提供了一种合理的方法。
Little is known regarding the functional effects of common autoimmune susceptibility variants on human immune cells. The SNIP CT60 (rs3087243; A/G) located in the 3' UTR of the CTLA4 gene has been associated with autoimmune diseases. We examined a cohort of healthy individuals stratified by genotypes at CTLA4 to gain insight into the functional effects of allelic variation on T cell signaling. Using phospho-site-specific mAbs, we tested the hypothesis that the CT60 genotype at CTLA4 is associated with altered T cell antigen receptor (TCR) signaling in naive and/or memory T cells. By normalizing for the extent of the initial TCR signaling event at CD3 zeta, we observed that the relative responsiveness to TCR stimulation as assessed by phosphorylation levels of downstream signaling molecules was altered in naive (CD4(+)CD45RA(high)) and memory (CD4(+)CD45RA(low)) T cells obtained from individuals with the disease-susceptibility allele at CTLA4. Thus, allelic variation associated with autoimmune disease can alter the signaling threshold of CD4(+) T cells. These experiments provide a rational approach for the dissection of T cell-susceptibility genes in autoimmune diseases.