CTLA-4 suppresses the pathogenicity of self antigen-specific T cells by cell-intrinsic and cell-extrinsic mechanisms.
CTLA-4 suppresses the pathogenicity of self antigen-specific T cells by cell-intrinsic and cell-extrinsic mechanisms.
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细胞毒性T淋巴细胞相关抗原4（CTLA - 4）在维持自身耐受方面至关重要，但其作用机制一直存在争议。在此，我们检测了CTLA - 4基因缺失（CTLA - 4−/−）小鼠中组织浸润的CD4 + T细胞的抗原特异性，并确定了CTLA - 4在体内的细胞靶点。组织浸润的CTLA - 4−/− T细胞表现出依赖T细胞受体（TCR）的归巢到其来源组织，这表明其对组织特异性抗原具有反应性。我们确定胰腺特异性酶蛋白二硫键异构酶A2（Pdia2）是CTLA - 4−/−小鼠中的一种自身抗原。在Pdia2特异性效应细胞或调节性T细胞（Tregs）上表达的CTLA - 4足以控制由Pdia2特异性T细胞介导的组织破坏。这些结果表明，CTLA - 4的细胞内在作用和细胞非自主作用在一种真正的自身抗原的调节环境中起作用，维持对该自身抗原的耐受需要CTLA - 4。
CTLA-4 is critical in maintaining self-tolerance but the mechanisms of its actions have been controversial. Here, we examined the antigen-specificity of tissue-infiltrating CD4+ T cells in CTLA-4−/− mice and determined the in vivo cellular targets of CTLA-4. Tissue-infiltrating CTLA-4−/− T cells exhibited TCR-dependent homing to their tissues of origin, suggesting reactivity against tissue-specific antigens. We identified the pancreas-specific enzyme Pdia2 as an autoantigen in CTLA-4−/− mice. CTLA-4 expressed either on Pdia2-specific effector cells, or on Tregs, was sufficient to control tissue destruction mediated by Pdia2-specific T cells. These results demonstrate that both cell-intrinsic and cell non-autonomous action of CTLA-4 operate in the context of regulation of an authentic self-antigen for which CTLA-4 is required to maintain tolerance.
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DOI：
10.1073/pnas.94.17.9296
发表时间：
1997-08-19
影响因子：
11.1
作者：
Chambers, CA;Cado, D;Allison, JP
通讯作者：
Allison, JP
影响因子：
56.9
作者：
Ostrov, DA;Shi, WX;Nathenson, SG
通讯作者：
Nathenson, SG
影响因子：
4.4
作者：
Kataoka, H;Takahashi, S;Saito, T
通讯作者：
Saito, T
影响因子：
30.5
作者：
Grohmann, U;Orabona, C;Puccetti, P
通讯作者：
Puccetti, P
DOI：
10.1073/pnas.96.15.8603
发表时间：
1999-07-20
影响因子：
11.1
作者：
Chambers, CA;Kuhns, MS;Allison, JP
通讯作者：
Allison, JP