CD4+ T Cell Tolerance to Tissue-Restricted Self Antigens Is Mediated by Antigen-Specific Regulatory T Cells Rather Than Deletion.
CD4+ T Cell Tolerance to Tissue-Restricted Self Antigens Is Mediated by Antigen-Specific Regulatory T Cells Rather Than Deletion.
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DOI：
10.1016/j.immuni.2015.10.011
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发表时间：
2015-11-17
期刊：
影响因子：
32.4
通讯作者：
Moon JJ
中科院分区：
文献类型：
--
作者：
Legoux FP;Lim JB;Cauley AW;Dikiy S;Ertelt J;Mariani TJ;Sparwasser T;Way SS;Moon JJ
胸腺发育过程中自身抗原特异性T细胞的缺失提供了对自身免疫的保护。然而，目前还不清楚这种情况如何有效地发生在组织限制性自身抗原，或者如何维持免疫耐受性的自身抗原特异性T细胞，通常逃避删除。在这里，我们表明，内源性的CD4+ T细胞与一组组织限制性自身抗原的特异性没有删除。对于胰腺自身抗原，这导致不存在稳态耐受性，而对于肺和肠，耐受性通过胸腺衍生的抗原特异性Foxp3+调节性T（Treg）细胞的存在增强来维持。与缺失性耐受不同，Treg细胞介导的耐受被连续的抗原攻击打破。这些发现表明，对于某些组织限制性自身抗原，耐受性完全依赖于非缺失机制，这种机制不如T细胞缺失持久。这可以解释为什么自身免疫通常是组织特异性的，并为靶向组织限制性肿瘤抗原的癌症疫苗策略提供了理论基础。
Deletion of self antigen-specific T cells during thymic development provides protection from autoimmunity. However, it is unclear how efficiently this occurs for tissue-restricted self antigens, or how immune tolerance is maintained for self antigen-specific T cells that routinely escape deletion. Here we show that endogenous CD4+ T cells with specificity for a set of tissue-restricted self antigens were not deleted at all. For pancreatic self antigen, this resulted in an absence of steady-state tolerance, while for the lung and intestine, tolerance was maintained by the enhanced presence of thymically-derived antigen-specific Foxp3+ regulatory T (Treg) cells. Unlike deletional tolerance, Treg cell-mediated tolerance was broken by successive antigen challenges. These findings reveal that for some tissue-restricted self antigens, tolerance relies entirely on nondeletional mechanisms that are less durable than T cell deletion. This may explain why autoimmunity is often tissue-specific, and offers a rationale for cancer vaccine strategies targeting tissue-restricted tumor antigens.