Mechanisms of CD4 T cell help for CD8 T cells during persistent viral infection

在病毒挑战之后，免疫系统未能控制和消除病毒，导致慢性感染。在许多慢性病毒感染中，病毒的持续会导致T细胞功能的丧失，称为“衰竭”。T细胞耗尽是许多病毒感染和肿瘤治疗和清除的障碍。一个复杂的遗传程序调节耗尽的T细胞抑制受体的表达，通过这些受体的信号调节它们较差的抗病毒功能。在慢性病毒感染期间，CD8细胞通过细胞与细胞的直接相互作用或分泌细胞因子，在维持CD8细胞的抗病毒功能、允许或改善病毒控制方面发挥关键作用。本研究的目的是确定在慢性病毒感染过程中，CD4帮助CD8T细胞的细胞和分子机制。淋巴细胞性脉络膜脑膜炎病毒(LCMV)将被用来研究慢性感染小鼠严重CD8T细胞耗尽后CD4T细胞的贡献。这些实验将被用来确定在慢性LCMV感染期间为CD8T细胞提供最佳帮助的细胞的功能特征和相关的CD4T辅助谱系。此外，还将研究在慢性感染期间接受CD4T细胞帮助的CD8T细胞恢复的抗病毒功能的功能和分子程序。

Following viral challenge, failure of the immune system to control and eliminate virus results in chronic infection. In many chronic viral infection, viral persistence drives the loss of T cell function, termed "exhaustion". T cell exhaustion represents an obstacle to the treatment and clearance of many viral infections and tumors. A complex genetic program regulates the expression of inhibitory receptors by exhausted T cells, and signaling through these receptors mediates their poor anti-viral function. CD4 T cells play a key role in providing help, through direct cell-cell interactions, or through the secretion of solule factors, to maintain the anti-viral function of CD8 cells during chronic viral infection, allowing or improved viral control. The objective of this study is to determine the cellular and molecular mechanisms for CD4 help provided to CD8 T cells during chronic viral infection. The well- characterized lymphocytic choriomeningitis virus (LCMV) will be used to investigate the contribution of CD4 T cells following severe CD8 T cell exhaustion in chronically infected mice. These experiments will be used to determine the functional characteristics and relevant CD4 T helper lineage of cells that provide optimal help to CD8 T cells during chronic LCMV infection. Furthermore, the functional and molecular program that regulates the restored anti-viral function of CD8 T cells that receive help from CD4 T cells during chronic infection will be investigated.