Department of Microbiology, George Washington University, Washington, DC 20037, USA.
Proc Natl Acad Sci U S A. 2011 May 31;108(22):9196-201. doi: 10.1073/pnas.1015298108. Epub 2011 May 16.
In this study, we document that Toxoplasma gondii differentiation and reactivation are mediated by systemic CD8 T-cell dysfunction during chronic infection. We demonstrate that CD8(+) T-cell exhaustion occurs despite control of parasitemia during early-chronic toxoplasmosis. During later phases, these cells become exhausted, leading to parasite reactivation and mortality. Concomitant with increased CD8(+) T-cell apoptosis and decreased effector response, this dysfunction is characterized by a graded elevation in expression of inhibitory receptor PD-1 on these cells in both lymphoid and nonlymphoid tissue. Blockade of the PD-1-PDL-1 pathway reinvigorates this suboptimal CD8(+) T-cell response, resulting in control of parasite reactivation and prevention of mortality in chronically infected animals. To the best of our knowledge, this report is unique in showing that exposure to a persistent pathogen despite initial control of parasitemia can lead to CD8(+) T-cell dysfunction and parasite reactivation.
在这项研究中，我们记录到，弓形虫的分化和重新激活是由慢性感染期间系统性 CD8 T 细胞功能障碍介导的。我们证明，尽管在早-慢性弓形虫病期间控制了寄生虫血症，但 CD8(+)T 细胞衰竭仍会发生。在后期，这些细胞衰竭，导致寄生虫重新激活和死亡。与增加的 CD8(+)T 细胞凋亡和减少的效应器反应同时发生，这种功能障碍的特征是在淋巴和非淋巴组织中这些细胞上抑制性受体 PD-1 的表达逐渐升高。阻断 PD-1-PDL-1 途径可重振这种次优的 CD8(+)T 细胞反应，从而控制寄生虫的重新激活，并防止慢性感染动物的死亡。据我们所知，本报告的独特之处在于，尽管最初控制了寄生虫血症，但接触持续性病原体仍可导致 CD8(+)T 细胞功能障碍和寄生虫重新激活。
