Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322.
Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 30322.
Proc Natl Acad Sci U S A. 2020 Feb 25;117(8):4292-4299. doi: 10.1073/pnas.1917298117. Epub 2020 Feb 7.
The migratory patterns of virus-specific CD8 T cells during chronic viral infection are not well understood. To address this issue, we have done parabiosis experiments during chronic lymphocytic choriomeningitis virus (LCMV) infection of mice. We found that despite the high frequency of virus-specific CD8 T cells in both lymphoid and nonlymphoid tissues there was minimal migration of virus-specific CD8 T cells between the chronically infected conjoined parabiont mice. This was in contrast to parabionts between mice that had undergone an acute LCMV infection where virus-specific CD8 T cells established equilibrium demonstrating circulation of memory T cells generated after viral clearance. We have identified a population of PD-1+ TCF1+CXCR5+Tim-3- stemlike virus-specific CD8 T cells that reside in lymphoid tissues and act as resource cells for maintaining the T cell response during chronic infection. These are the cells that proliferate and give rise to the more terminally differentiated PD-1+ CXCR5-Tim-3+ CD8 T cells. Both the stemlike CD8 T cells and their terminally differentiated progeny showed minimal migration during chronic infection and the few LCMV-specific CD8 T cells that were present in circulation were the recently emerging progeny from the stemlike CD8 T cells. The PD-1+ TCF1+CXCR5+ stemlike CD8 T cells were truly resident in lymphoid tissues and did not circulate in the blood. We propose that this residency in specialized niches within lymphoid tissues is a key aspect of their biology and is essential for maintaining their quiescence and stemlike program under conditions of a chronic viral infection.
慢性病毒感染期间病毒特异性 CD8 T 细胞的迁移模式尚不清楚。为了解决这个问题，我们在慢性淋巴细胞脉络丛脑膜炎病毒 (LCMV) 感染小鼠期间进行了联体共生实验。我们发现，尽管淋巴样和非淋巴样组织中病毒特异性 CD8 T 细胞的频率很高，但慢性感染联体共生小鼠之间病毒特异性 CD8 T 细胞的迁移很少。这与经历急性 LCMV 感染的共生小鼠形成对比，在急性感染中，病毒特异性 CD8 T 细胞建立了平衡，表明清除病毒后产生的记忆 T 细胞循环。我们已经鉴定出一群 PD-1+TCF1+CXCR5+Tim-3-CD8 T 细胞，它们存在于淋巴组织中，作为维持慢性感染期间 T 细胞反应的资源细胞。这些细胞增殖并产生更多终末分化的 PD-1+CXCR5-Tim-3+CD8 T 细胞。在慢性感染期间，这些干细胞样 CD8 T 细胞及其终末分化的后代都表现出很少的迁移，而循环中存在的少数 LCMV 特异性 CD8 T 细胞是来自干细胞样 CD8 T 细胞的最近出现的后代。PD-1+TCF1+CXCR5+干细胞样 CD8 T 细胞确实存在于淋巴组织中，不会在血液中循环。我们提出，这种在淋巴组织内特定小生境中的驻留是其生物学的一个关键方面，对于在慢性病毒感染条件下维持其静止和干细胞样程序是必不可少的。
