Peripheral CD8+ T cell tolerance to self-proteins is regulated proximally at the T cell receptor
Peripheral CD8+ T cell tolerance to self-proteins is regulated proximally at the T cell receptor
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DOI：
10.1016/j.immuni.2008.03.012
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发表时间：
2008-05-01
期刊：
影响因子：
32.4
通讯作者：
Oehlen, Claes
中科院分区：
文献类型：
--
作者：
Teague, Ryan M.;Greenberg, Philip D.;Oehlen, Claes
尽管CD8（+）T细胞耐受性对于预防自身免疫是必不可少的，但对引发对肿瘤抗原的免疫应答构成实质性障碍，肿瘤抗原通常是过表达的正常蛋白质。阐明调节T细胞对自身耐受性的免疫学机制将有助于开发克服耐受性的有效策略以用于临床应用。为了研究如何在体内维持耐受性，我们设计了双T细胞受体（TCR）转基因小鼠，其中CD8（+）T细胞识别两种不同的抗原：外源病毒蛋白和耐受性自身肿瘤蛋白。与外周自身抗原的接触使双TCR T细胞对自身耐受，但这些细胞通过病毒特异性TCR正常应答。此外，由病毒诱导的增殖挽救了耐受的自身肿瘤反应性TCR的功能，恢复了抗肿瘤活性。这些研究表明，外周CD8（+）T细胞对自身蛋白的耐受性可以在自身反应性TCR复合物的水平上调节，而不是通过中枢细胞失活，并提出了增强过继性T细胞免疫治疗的替代策略。
CD8(+) T cell tolerance, although essential for preventing autoimmunity, poses substantial obstacles to eliciting immune responses to tumor antigens, which are generally overexpressed normal proteins. Development of effective strategies to overcome tolerance for clinical applications would benefit from elucidation of the immunologic mechanism(s) regulating T cell tolerance to self. To examine how tolerance is maintained in vivo, we engineered dual-T cell receptor (TCR) transgenic mice in which CD8(+) T cells recognize two distinct antigens: a foreign viral-protein and a tolerizing self-tumor protein. Encounter with peripheral self-antigen rendered dual-TCR T cells tolerant to self, but these cells responded normally through the virus-specific TCR. Moreover, proliferation induced by virus rescued function of tolerized self-tumor-reactive TCR, restoring anti-tumor activity. These studies demonstrate that peripheral CD8(+) T cell tolerance to self-proteins can be regulated at the level of the self-reactive TCR complex rather than by central cellular inactivation and suggest an alternate strategy to enhance adoptive T cell immunotherapy.