PD-L1, TIM-3, and CTLA-4 Blockade Fails To Promote Resistance to Secondary Infection with Virulent Strains of Toxoplasma gondii.
PD-L1, TIM-3, and CTLA-4 Blockade Fails To Promote Resistance to Secondary Infection with Virulent Strains of Toxoplasma gondii.
复制标题
PD-L1、TIM-3 和 CTLA-4 阻断无法促进对弓形虫毒株继发感染的抵抗力。
DOI：
10.1128/iai.00459-18
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发表时间：
2018
影响因子：
3.1
通讯作者：
Jensen,KirkDC
中科院分区：
文献类型：
--
作者：
Splitt,SamanthaD;Souza,ScottP;Valentine,KristenM;Castellanos,BrayanE;Curd,AndrewB;Hoyer,KatrinaK;Jensen,KirkDC
T细胞耗竭是在许多慢性感染和癌症期间出现的一种低反应状态。中和抑制性受体，或“检查点阻断”，可以扭转T细胞枯竭，并在实验和临床环境中导致有利的预后。检查点封锁是否可以解决致命的急性感染尚不清楚，但在未能引发灭菌免疫的疫苗接种方案中可能是有益的。由于针对任何人类寄生虫的完全保护性疫苗尚未开发出来，我们探索了检查点抑制剂在弓形虫再感染小鼠模型中的有效性。长期感染无毒III型毒株的小鼠在I型RH毒株的再感染中存活下来，但不能感染MAS、Guy-DOS和GT1寄生虫毒株。我们在此报告，小鼠对继发感染的敏感性与初始寄生虫负荷有关，在该模型中，对RH株的保护依赖于CD8，而不是CD4T细胞。当受到致命的继发感染时，CD8和CD4T细胞上调几种共抑制受体，包括PD-1、TIM-3、4-1BB和CTLA-4。此外，在二次感染强毒株期间，CD8T细胞的干扰素(干扰素-γ)反应显著降低，这表明检查点封锁可能会降低疾病的严重程度。然而，针对TIM-3、CTLA-4和/或PD-L1的单一和联合治疗未能逆转继发感染的易感性。这些结果表明，对这种病原体的免疫可能需要更多的宿主反应，这些反应对检查点封锁是无效的。
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 Toxoplasma gondii 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.