Molecular and Cell Biology Department, School of Natural Sciences, University of California, Merced, Merced, California, USA.
Molecular and Cell Biology Department, School of Natural Sciences, University of California, Merced, Merced, California, USA
Infect Immun. 2018 Aug 22;86(9). doi: 10.1128/IAI.00459-18. Print 2018 Sep.
T cell exhaustion is a state of hyporesponsiveness that develops during many chronic infections and cancer. Neutralization of inhibitory receptors, or "checkpoint blockade," can reverse T cell exhaustion and lead to beneficial prognoses in experimental and clinical settings. Whether checkpoint blockade can resolve lethal acute infections is less understood but may be beneficial in vaccination protocols that fail to elicit sterilizing immunity. Since a fully protective vaccine for any human parasite has yet to be developed, we explored the efficacy of checkpoint inhibitors in a mouse model of reinfection. Mice chronically infected with an avirulent type III strain survive reinfection with the type I RH strain but not the MAS, GUY-DOS, and GT1 parasite strains. We report here that mouse susceptibility to secondary infection correlates with the initial parasite burden and that protection against the RH strain is dependent on CD8 but not CD4 T cells in this model. When given a lethal secondary infection, CD8 and CD4 T cells upregulate several coinhibitory receptors, including PD-1, TIM-3, 4-1bb, and CTLA-4. Moreover, the gamma interferon (IFN-γ) response of CD8 but not CD4 T cells is significantly reduced during secondary infection with virulent strains, suggesting that checkpoint blockade may reduce disease severity. However, single and combination therapies targeting TIM-3, CTLA-4, and/or PD-L1 failed to reverse susceptibility to secondary infection. These results suggest that additional host responses, which are refractory to checkpoint blockade, are likely required for immunity to this pathogen.
T 细胞耗竭是一种低反应性状态，在许多慢性感染和癌症中发展。抑制性受体的中和，或“检查点阻断”，可以逆转 T 细胞耗竭，并在实验和临床环境中导致有益的预后。检查点阻断是否可以解决致命的急性感染尚不清楚，但在未能引起杀菌性免疫的疫苗接种方案中可能是有益的。由于尚未开发出针对任何人类寄生虫的完全保护性疫苗，我们在小鼠再感染模型中探索了检查点抑制剂的疗效。慢性感染无毒性 III 型菌株的小鼠可以存活再感染 I 型 RH 株，但不能存活 MAS、GUY-DOS 和 GT1 寄生虫株的再感染。我们在这里报告，小鼠对二次感染的易感性与初始寄生虫负荷相关，并且在该模型中，对 RH 株的保护依赖于 CD8 而不是 CD4 T 细胞。当发生致命的二次感染时，CD8 和 CD4 T 细胞上调几种共抑制受体，包括 PD-1、TIM-3、4-1bb 和 CTLA-4。此外，在感染毒性菌株时，CD8 但不是 CD4 T 细胞的γ干扰素（IFN-γ）反应显著降低，表明检查点阻断可能降低疾病严重程度。然而，针对 TIM-3、CTLA-4 和/或 PD-L1 的单一和联合治疗未能逆转对二次感染的易感性。这些结果表明，对于这种病原体的免疫，可能需要宿主的其他反应，这些反应对检查点阻断有抗性。
