Induction of autoimmune disease by deletion of CTLA-4 in mice in adulthood
Induction of autoimmune disease by deletion of CTLA-4 in mice in adulthood
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DOI：
10.1073/pnas.1603892113
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发表时间：
2016-04-26
影响因子：
11.1
通讯作者：
Wing, Kajsa
中科院分区：
文献类型：
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作者：
Klocke, Katrin;Sakaguchi, Shimon;Wing, Kajsa
细胞毒性T淋巴细胞抗原-4 （CTLA-4）对免疫（自我）耐受至关重要，但由于CTLA-4 KO小鼠的早期死亡，其在中枢和外周耐受以及不同全身性疾病中的特异性功能仍有待确定。在这里，我们通过在成年小鼠中去除CTLA-4的表达进一步研究了CTLA-4的作用，并比较了由此产生的自身免疫与先天性CTLA-4缺乏所产生的自身免疫。我们发现CTLA-4在成年小鼠中的条件性缺失导致自发性淋巴细胞增殖、高γ球蛋白血症和组织学上明显的肺炎、胃炎、胰岛素炎和涎腺炎，并伴有器官特异性自身抗体。然而，与先天性缺陷相比，这并不是致命的。CTLA-4缺失诱导CD4(+) Foxp3(+) Treg细胞优先扩增。然而，来自ctla -4缺陷诱导型KO小鼠的T细胞能够过继性地将疾病转移到T细胞缺陷小鼠中。值得注意的是，新生胸腺细胞的细胞转移产生心肌炎，否则在成年后耗尽的供体小鼠中没有观察到。此外，CTLA-4缺失在成年小鼠中对诱导的自身免疫模型有相反的影响。因此，尽管ctla -4缺陷小鼠有更严重的胶原诱导关节炎（CIA），但它们对肽诱导的实验性自身免疫性脑脊髓炎（EAE）有保护作用；然而，蛋白质诱导的EAE的发作只是延迟。总的来说，这表明CTLA-4缺陷影响中枢和外周耐受性和Treg细胞介导的抑制。
Cytotoxic T lymphocyte antigen-4 (CTLA-4) is essential for immunological (self-) tolerance, but due to the early fatality of CTLA-4 KO mice, its specific function in central and peripheral tolerance and in different systemic diseases remains to be determined. Here, we further examined the role of CTLA-4 by abrogating CTLA-4 expression in adult mice and compared the resulting autoimmunity that follows with that produced by congenital CTLA-4 deficiency. We found that conditional deletion of CTLA-4 in adult mice resulted in spontaneous lymphoproliferation, hypergammaglobulinemia, and histologically evident pneumonitis, gastritis, insulitis, and sialadenitis, accompanied by organ-specific autoantibodies. However, in contrast to congenital deficiency, this was not fatal. CTLA-4 deletion induced preferential expansion of CD4(+) Foxp3(+) Treg cells. However, T cells from CTLA-4-deficient inducible KO mice were able to adoptively transfer the diseases into T cell-deficient mice. Notably, cell transfer of thymocytes de novo produced myocarditis, otherwise not observed in donor mice depleted in adulthood. Moreover, CTLA-4 deletion in adult mice had opposing impacts on induced autoimmune models. Thus, although CTLA-4-deficient mice had more severe collagen-induced arthritis (CIA), they were protected against peptide-induced experimental autoimmune encephalomyelitis (EAE); however, onset of protein-induced EAE was only delayed. Collectively, this indicates that CTLA-4 deficiency affects both central and peripheral tolerance and Treg cell-mediated suppression.