Control of Toxoplasma reactivation by rescue of dysfunctional CD8+ T-cell response via PD-1-PDL-1 blockade

被引:122
作者
Bhadra, Rajarshi [1 ]
Gigley, Jason P. [1 ]
Weiss, Louis M. [2 ]
Khan, Imtiaz A. [1 ]
机构
[1] George Washington Univ, Dept Microbiol Immunol & Trop Med, Washington, DC 20037 USA
[2] Albert Einstein Coll Med, Dept Pathol & Med, Bronx, NY 10461 USA
基金
美国国家卫生研究院;
关键词
recrudescence; Toxoplasma gondii; adaptive immunity; CHRONIC VIRAL-INFECTION; INDUCIBLE NITRIC-OXIDE; CEREBRAL TOXOPLASMOSIS; TRANSCRIPTION FACTOR; ORAL-TRANSMISSION; GONDII; EFFECTOR; MEMORY; AIDS; ENCEPHALITIS;
D O I
10.1073/pnas.1015298108
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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.
引用
收藏
页码:9196 / 9201
页数:6
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