A role for perforin in downregulating T-cell responses during chronic viral infection
A role for perforin in downregulating T-cell responses during chronic viral infection
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DOI：
10.1128/jvi.73.3.2527-2536.1999
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发表时间：
1999-03-01
影响因子：
5.4
通讯作者：
Ahmed, R
中科院分区：
文献类型：
--
作者：
Matloubian, M;Suresh, M;Ahmed, R
细胞毒性T细胞分泌穿孔素杀死病毒感染的细胞。在这项研究中，我们发现穿孔素也在免疫调节中发挥作用。与持续感染的+/+小鼠相比，慢性感染淋巴细胞性脉络丛脑膜炎病毒（LCMV）的穿孔素缺乏（perf -/-）小鼠含有更多的抗病毒T细胞。在CD4和CD8 T细胞中均可见增强的扩增，但最显著的差异是感染的perf -/-小鼠中存在lcmv特异性CD8 T细胞的数量。LCMV持续感染+/+小鼠导致抗原特异性CD8 T细胞的缺失和能量，我们的研究结果表明，活化CD8 T细胞的外周“耗竭”在perf -/-小鼠中发生的效率较低。在持续感染的perf -/-小鼠中，活化CD8 T细胞的过度积累导致免疫介导的损伤；大约50%的小鼠在2至4周内死亡，并且通过体内消耗CDS T细胞完全逆转了死亡。这一发现突出了穿孔素在病毒清除和免疫病理中的作用之间的一个有趣的二分法；穿孔素缺陷的CD8 T细胞不能清除LCMV感染，但能够引起免疫介导的损伤。最后，本研究表明穿孔素也在调节t细胞介导的自身免疫中发挥作用。穿孔素和Fas均缺乏的小鼠表现出Fas缺乏（lpr）小鼠中自发淋巴增生性疾病的显著加速。综上所述，这些结果表明，在慢性病毒感染和自身免疫过程中，穿孔素介导的途径参与了T细胞反应的下调，穿孔素和Fas分别作为活化T细胞的负调节因子。
Cytotoxic T cells secrete perforin to kill virus-infected cells. In this study we show that perforin also plays a role in immune regulation. Perforin-deficient (perf -/-) mice chronically infected with lymphocytic choriomeningitis virus (LCMV) contained greater numbers of antiviral T cells compared to persistently infected +/+ mice. The enhanced expansion was seen in both CD4 and CD8 T cells, but the most striking difference was in the numbers of LCMV-specific CD8 T cells present in infected perf -/- mice. Persistent LCMV infection of +/+ mice results in both deletion and anergy of antigen-specific CD8 T cells, and our results show that this peripheral "exhaustion" of activated CD8 T cells occurred less efficiently in perf -/- mice. This excessive accumulation of activated CD8 T cells resulted in immune-mediated damage in persistently infected perf -/- mice; similar to 50% of these mice died within 2 to 4 weeks, and mortality was fully reversed by in vivo depletion of CDS T cells. This finding highlights an interesting dichotomy between the role of perforin in viral clearance and immunopathology; perforin-deficient CD8 T cells were unable to clear the LCMV infection but were capable of causing immune-mediated damage. Finally, this study shows that perforin also plays a role in regulating T-cell-mediated autoimmunity. Mice that were deficient in both perforin and Fas exhibited a striking acceleration of the spontaneous lymphoproliferative disease seen in Fas-deficient (lpr) mice. Taken together, these results show that the perforin-mediated pathway is involved in downregulating T-cell responses during chronic viral infection and autoimmunity and that perforin and Fas act independently as negative regulators of activated T cells.