Perforin is a critical physiologic regulator of T-cell activation
Perforin is a critical physiologic regulator of T-cell activation
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DOI：
10.1182/blood-2010-12-324533
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发表时间：
2011-07-21
期刊：
影响因子：
20.3
通讯作者：
Jordan, Michael B.
中科院分区：
文献类型：
--
作者：
Lykens, Jennifer E.;Terrell, Catherine E.;Jordan, Michael B.
穿孔素依赖性细胞毒性功能受损（Ctx（-））的个体会发生一种称为噬血细胞性淋巴组织细胞增多症（HLH）的致命性炎症性疾病。据推测，HLH期间的免疫超活化是由感染加剧、Ctx（-）淋巴细胞的凋亡/反应缺陷或抗原呈递增强引起的。尽管临床和实验数据表明，增加的T细胞活化驱动HLH，但在Ctx（-）宿主中尚未充分表征T细胞活化的潜在异常。为了确定这种异常并检验这些假设，我们评估了Ctx（-）小鼠淋巴细胞性脉络丛脑膜炎病毒（LCMV）感染后体内T细胞活化动力学和病毒载量。我们发现，在Ctx（-）小鼠感染期间，T细胞活化增加发生在早期，而它们的病毒负荷与WT动物相同，这表明T细胞过度活化与病毒负荷无关。此外，细胞转移和信号传导研究表明，抗原刺激的增加，而不是细胞内在的反应缺陷，是体内T细胞活化增强的基础。最后，病毒抗原呈递的直接测量表明Ctx（-）小鼠的增加与异常T细胞活化成比例。我们得出结论，穿孔素依赖的细胞毒性具有免疫调节作用，这是区别于其病原体清除功能和限制T细胞活化的生理背景下，通过抑制抗原呈递。（血。2011;118（3）：618-626）
Individuals with impaired perforin-dependent cytotoxic function (Ctx(-)) develop a fatal inflammatory disorder called hemophagocytic lymphohistiocytosis (HLH). It has been hypothesized that immune hyperactivation during HLH is caused by heightened infection, defective apoptosis/responsiveness of Ctx(-) lymphocytes, or enhanced antigen presentation. Whereas clinical and experimental data suggest that increased T-cell activation drives HLH, potential abnormalities of T-cell activation have not been well characterized in Ctx(-) hosts. To de-fine such abnormalities and to test these hypotheses, we assessed in vivo T-cell activation kinetics and viral loads after lymphocytic choriomeningitis virus (LCMV) infection of Ctx(-) mice. We found that increased T-cell activation occurred early during infection of Ctx(-) mice, while they had viral burdens that were identical to those of WT animals, demonstrating that T-cell hyperactivation was independent of viral load. Furthermore, cell transfer and signaling studies indicated that increased antigenic stimulation, not a cell-intrinsic defect of responsiveness, underlay heightened T-cell activation in vivo. Finally, direct measurement of viral antigen presentation demonstrated an increase in Ctx(-) mice that was proportional to abnormal T-cell activation. We conclude that perforin-dependent cytotoxicity has an immunoregulatory role that is distinguishable from its pathogen clearance function and limits T-cell activation in the physiologic context by suppressing antigen presentation. (Blood. 2011;118(3):618-626)