Expansion of dysfunctional Tim-3-expressing effector memory CD8+ T cells during simian immunodeficiency virus infection in rhesus macaques.
Expansion of dysfunctional Tim-3-expressing effector memory CD8+ T cells during simian immunodeficiency virus infection in rhesus macaques.
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DOI：
10.4049/jimmunol.1400961
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发表时间：
2014-12-01
期刊：
影响因子：
--
通讯作者：
Ndhlovu LC
中科院分区：
文献类型：
--
作者：
Fujita T;Burwitz BJ;Chew GM;Reed JS;Pathak R;Seger E;Clayton KL;Rini JM;Ostrowski MA;Ishii N;Kuroda MJ;Hansen SG;Sacha JB;Ndhlovu LC
T 细胞免疫球蛋白和含有粘蛋白结构域的分子 (Tim)-3 阴性免疫检查点受体界定了因 HIV 等病毒感染的慢性刺激而产生的功能耗尽的 CD8+ T 细胞。 Tim-3 阻断可改善体外抗病毒 CD8+ T 细胞反应，因此代表了一种恢复体内 T 细胞功能并防止疾病进展的新干预策略。然而，生理相关的 AIDS 恒河猴 SIV 模型中的 Tim-3 通路仍未得到表征。我们在此报告，在 SIV 感染的动物中，淋巴结中的 Tim-3+CD8+ T 细胞频率显着增加，但外周血中没有显着增加。 Tim-3+PD-1+CD8+ T 细胞在 SIV 感染期间同样增加，并与 SIV 血浆病毒血症呈正相关。在所有检查的组织中，Tim-3 表达主要出现在效应记忆 CD8+ T 细胞上。与 Tim-3−CD8+ T 细胞相比，Tim-3+CD8+ T 细胞具有较低的 Ki-67 含量和对 SIV 的最小细胞因子反应。在 SIV 复制急性期期间，感染后 2 周，Tim-3 表达在 SIV 特异性 CD8+ T 细胞上达到峰值，然后迅速减少，无论同源抗原是否发生突变逃逸，这表明 Tim-3 表达的非 TCR 驱动机制。因此，SIV 感染中的恒河猴 Tim-3 部分模仿了 HIV 感染中的人类 Tim-3，并且可以作为专注于恢复 HIV 特异性 CD8+ T 细胞反应的靶向研究的新模型。
The T cell immunoglobulin- and mucin domain-containing molecule (Tim)-3 negative immune checkpoint receptor demarcates functionally exhausted CD8+ T cells arising from chronic stimulation in viral infections like HIV. Tim-3 blockade leads to improved anti-viral CD8+ T cell responses in vitro and therefore represents a novel intervention strategy to restore T cell function in vivo and protect from disease progression. However, the Tim-3 pathway in the physiologically relevant rhesus macaque SIV model of AIDS remains uncharacterized. We report here that Tim-3+CD8+ T cell frequencies are significantly increased in lymph nodes, but not in peripheral blood, in SIV-infected animals. Tim-3+PD-1+CD8+ T cells are similarly increased during SIV infection and positively correlate with SIV plasma viremia. Tim-3 expression was found primarily on effector memory CD8+ T cells in all tissues examined. Tim-3+CD8+ T cells have lower Ki-67 content and minimal cytokine responses to SIV compared to Tim-3−CD8+ T cells. During acute phase SIV replication Tim-3 expression peaked on SIV-specific CD8+ T cells by 2 weeks post infection, and then rapidly diminished irrespective of mutational escape of cognate antigen, suggesting non-TCR driven mechanisms for Tim-3 expression. Thus, rhesus Tim-3 in SIV infection partially mimics human Tim-3 in HIV infection and may serve as a novel model for targeted studies focused on rejuvenating HIV-specific CD8+ T cell responses.
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