An exhaustion-like phenotype constrains the activity of CD4+ T cells specific for a self and melanoma antigen.
An exhaustion-like phenotype constrains the activity of CD4+ T cells specific for a self and melanoma antigen.
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DOI：
10.1371/journal.pone.0123332
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Hastings KT
中科院分区：
文献类型：
--
作者：
Rausch MP;Hastings KT
虽然免疫系统有能力识别和破坏黑色素瘤，但耐受机制通常会阻碍有效抗肿瘤免疫反应的发展。由于许多黑色素瘤抗原是在正常黑色素细胞中表达的自身蛋白，因此在肿瘤发展之前暴露自身抗原可负面影响对这些自身/肿瘤抗原特异性的T细胞的功能。然而，自身耐受性对抗黑色素瘤T细胞功能障碍的贡献在很大程度上仍未被探索。我们先前已经描述了TCR转基因（Tg）小鼠模型，其中对自身/黑素瘤抗原酪氨酸酶相关蛋白1（TRP 1）具有特异性的T细胞在内源性TRP 1表达（Ag+）和由于缺乏γ-干扰素诱导型溶酶体巯基还原酶（GILT-/-）而导致的抗原呈递减少的情况下发育。我们发现，与来自Ag-GILT+/+Tg小鼠的T细胞相比，来自这些Ag+GILT-/-Tg小鼠的TRP 1特异性T细胞不能防止黑色素瘤肿瘤生长，不能诱导自身免疫性白癜风，并且增殖减少。尽管与Ag-GILT+/+Tg动物相比，Ag+GILT-/-Tg小鼠中TRP 1特异性Treg细胞的频率增加，但Treg细胞耗竭仅部分挽救了TRP 1表达小鼠T细胞的增殖能力，表明涉及其他抑制机制。来自Ag+GILT-/-Tg动物的黑素瘤特异性T细胞的百分比增加表达PD-1，PD-1是与维持T细胞耗竭相关的抑制性受体。PD-1的抗体阻断部分提高了来自Ag+GILT-/-Tg小鼠的TRP 1特异性T细胞产生IL-2的能力。这些发现表明，在健康组织中暴露于自身/黑色素瘤抗原的黑色素瘤特异性T细胞在遇到肿瘤之前发展出以PD-1介导的免疫抑制为特征的耗竭样表型。
While the immune system has the capacity to recognize and destroy melanoma, tolerance mechanisms often hinder the development of effective anti-tumor immune responses. Since many melanoma antigens are self proteins expressed in normal melanocytes, self antigen exposure before tumor development can negatively impact the function of T cells specific for these self/tumor antigens. However, the contribution of self tolerance to anti-melanoma T cell dysfunction remains largely unexplored. We have previously described a TCR transgenic (Tg) mouse model in which T cells specific for the self/melanoma antigen, tyrosinase-related protein 1 (TRP1), develop in the presence of endogenous TRP1 expression (Ag+) and diminished antigen presentation due to the absence of gamma-interferon-inducible lysosomal thiol reductase (GILT-/-). We show that TRP1-specific T cells from these Ag+GILT-/-Tg mice do not protect from melanoma tumor growth, fail to induce autoimmune vitiligo, and undergo diminished proliferation compared to T cells from Ag-GILT+/+Tg mice. Despite an increased frequency of TRP1-specific Treg cells in Ag+GILT-/-Tg mice compared to Ag-GILT+/+Tg animals, Treg cell depletion only partially rescues the proliferative capacity of T cells from TRP1-expressing mice, suggesting the involvement of additional suppressive mechanisms. An increased percentage of melanoma-specific T cells from Ag+GILT-/-Tg animals express PD-1, an inhibitory receptor associated with the maintenance of T cell exhaustion. Antibody blockade of PD-1 partially improves the ability of TRP1-specific T cells from Ag+GILT-/-Tg mice to produce IL-2. These findings demonstrate that melanoma-specific T cells exposed to a self/melanoma antigen in healthy tissue develop an exhaustion-like phenotype characterized by PD-1-mediated immunosuppression prior to encounter with tumor.
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DOI：
10.1126/science.1159407
发表时间：
2008-08-08
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Gardner JM;Devoss JJ;Friedman RS;Wong DJ;Tan YX;Zhou X;Johannes KP;Su MA;Chang HY;Krummel MF;Anderson MS
通讯作者：
Anderson MS
影响因子：
3.9
作者：
Parkhurst, MR;Riley, JP;Rosenberg, SA
通讯作者：
Rosenberg, SA
影响因子：
6.5
作者：
Rausch, Matthew P.;Hastings, K. Taraszka
通讯作者：
Hastings, K. Taraszka
DOI：
10.1084/jem.20100643
发表时间：
2010-09-27
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Sakuishi K;Apetoh L;Sullivan JM;Blazar BR;Kuchroo VK;Anderson AC
通讯作者：
Anderson AC
影响因子：
56.9
作者：
Maric, M;Arunachalam, B;Cresswell, P
通讯作者：
Cresswell, P