Cytotoxic T lymphocyte antigen-4 (CTLA-4) regulates primary and secondary peptide-specific CD4+ T cell responses
Cytotoxic T lymphocyte antigen-4 (CTLA-4) regulates primary and secondary peptide-specific CD4+ T cell responses
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DOI：
10.1073/pnas.96.15.8603
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发表时间：
1999-07-20
影响因子：
11.1
通讯作者：
Allison, JP
中科院分区：
文献类型：
--
作者：
Chambers, CA;Kuhns, MS;Allison, JP
CTLA - 4缺陷型小鼠会发生一种致命的淋巴细胞增殖性疾病，其特征是外周淋巴细胞的多克隆扩增。为了研究限制CD4(+)T细胞受体库对CTLA - 4缺陷型小鼠表型的影响，并评估CTLA - 4在体外对肽特异性CD4(+)T细胞反应的影响，将一种MHC II类限制性T细胞受体（AND TCR）转基因导入CTLA - 4(-/-)动物体内。CD4(+)T细胞表达AND TCR转基因会延迟但不能阻止CTLA - 4(-/-)小鼠的淋巴细胞增殖。CD4(+)T细胞优先被激活并扩增。有趣的是，携带rag - 1基因无效突变的年轻AND TCR+ CTLA - 4(-/-)小鼠保持健康，并且T细胞在生命后期之前一直保持初始表型。我们证明CTLA - 4在体外调节初始的以及先前被激活的AND TCR+ RAG(-/-)T细胞产生的肽特异性增殖反应。CTLA - 4的缺失也会增加分泌细胞因子的AND TCR+ RAG(-/-)T细胞的反应频率。这些结果表明CTLA - 4是肽特异性CD4(+)T细胞反应的关键调节因子，并支持CTLA - 4在维持CD4(+)与CD8(+)T细胞的T细胞稳态中起不同作用的模型。
CTLA-4-deficient mice develop a fatal lymphoproliferative disorder, characterized by polyclonal expansion of peripheral lymphocytes. To examine the effect of restricting the CD4(+) TCR repertoire on the phenotype of CTLA-4-deficient mice and to assess the influence of CTLA-4 on peptide-specific CD4(+) T cell responses in vitro, an MHC class II-restricted T cell receptor (AND TCR) transgene was introduced into the CTLA-4(-/-) animals. The expression of the AND TCR transgene by CD4(+) T cells delays but does not prevent the lymphoproliferation in the CTLA-4(-/-) mice. The CD4(+) T cells become preferentially activated and expand. Interestingly, young AND TCR+ CTLA-4(-/-) mice carrying a null mutation in the rag-1 gene remain healthy and the T cells maintain a naive phenotype until later in life. We demonstrate that CTLA-4 regulates the peptide-specific proliferative response generated by naive and previously activated AND TCR+ RAG(-/-) T cells in vitro. The absence of CTLA-4 also augments the responder frequency of cytokine-secreting AND TCR+ RAG(-/-) T cells. These results demonstrate that CTLA-4 is a keg regulator of peptide specific CD4(+) T cell responses and support the model that CTLA-4 plays a differential role in maintaining T cell homeostasis of CD4(+) vs. CD8(+) T cells.