High antigen levels are the cause of T cell exhaustion during chronic viral infection
High antigen levels are the cause of T cell exhaustion during chronic viral infection
复制标题
DOI：
10.1073/pnas.0809818106
复制
发表时间：
2009-05-26
影响因子：
11.1
通讯作者：
Ahmed, Rafi
中科院分区：
文献类型：
--
作者：
Mueller, Scott N.;Ahmed, Rafi
许多持续的病毒感染会引起功能失调的T细胞反应。尽管在慢性感染期间病毒载量和T细胞反应之间存在负相关，但目前尚不清楚高抗原水平是T细胞耗尽的原因还是结果。此外，骨髓(BM)来源的抗原提呈与感染的实质细胞相比在T细胞耗竭方面的作用尚不清楚。为了解决这些问题，我们检测了在淋巴细胞脉络膜脑膜炎病毒(LCMV)克隆13持续感染小鼠过程中，不同细胞类型的抗原提呈对CD8(+)T细胞反应的影响。我们产生了BM嵌合小鼠，其中非BM来源细胞是MHC I类缺陷细胞。感染后不久，淋巴组织和非淋巴组织中的病毒特异性CD8(+)T细胞的数量和产生细胞因子的能力都增加。然而，尽管产生CTL的细胞因子数量增加，但从受感染的MHC I-/-实质组织中清除病毒的能力受到显著损害。CD8(+)T细胞反应被持续的抗原持久性压倒，在4-6周内逐渐耗尽。因此，我们发现(I)在慢性病毒感染期间，持续的抗原提呈直接导致T细胞耗竭，(Ii)CTL需要直接的抗原-MHC相互作用来清除病毒感染的细胞，以及(Iii)在慢性感染期间，与造血和非造血细胞上的抗原的持续相互作用对病毒特异性T细胞反应产生负面影响。
Many persistent viral infections induce dysfunctional T cell responses. Although a negative correlation exists between viral load and T cell responses during chronic infection, it is not known whether high antigen levels are the cause or just the consequence of T cell exhaustion. Furthermore, it is unclear what role antigen presentation by bone-marrow (BM) derived versus infected parenchymal cells has on T cell exhaustion. To address these issues, we examined the influence of antigen presentation by different cell types on CD8(+) T cell responses during persistent infection of mice with lymphocytic choriomeningitis virus (LCMV) clone 13. We generated BM chimeric mice, in which non-BM derived cells were MHC class I deficient. Virus-specific CD8(+) T cells in lymphoid and nonlymphoid tissues were increased in both number and ability to produce cytokines in these mice soon after infection. However, viral clearance from infected MHC I-/- parenchyma was significantly impaired, despite increased populations of cytokine producing CTL. The CD8(+) T cell response was overwhelmed by sustained antigen persistence, becoming increasingly exhausted within 4-6 weeks. Thus, we find that (i) sustained antigen presentation directly drives T cell exhaustion during a chronic viral infection, (ii) CTL require direct antigen-MHC interactions to clear virus-infected cells, and (iii) persistent interactions with antigen presented on both hematopoietic and nonhematopoietic cells negatively impacts virus-specific T cell responses during chronic infection.