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

病毒攻击后，免疫系统无法控制和消除病毒，导致慢性感染。在许多慢性病毒感染中，病毒持续存在导致T细胞功能丧失，称为“衰竭”。T细胞耗竭代表了许多病毒感染和肿瘤的治疗和清除的障碍。一个复杂的遗传程序通过耗尽的T细胞调节抑制性受体的表达，并且通过这些受体的信号传导介导其不良的抗病毒功能。CD 4 T细胞通过直接的细胞-细胞相互作用或通过可溶性因子的分泌在提供帮助方面发挥关键作用，以在慢性病毒感染期间维持CD 8细胞的抗病毒功能，从而允许或改善病毒控制。本研究的目的是确定在慢性病毒感染过程中CD 4帮助CD 8 T细胞的细胞和分子机制。充分表征的淋巴细胞性脉络丛脑膜炎病毒（LCMV）将用于研究慢性感染小鼠中严重的CD 8 T细胞耗竭后CD 4 T细胞的贡献。这些实验将用于确定在慢性LCMV感染期间为CD 8 T细胞提供最佳帮助的细胞的功能特征和相关CD 4 T辅助细胞谱系。此外，将研究调节在慢性感染期间接受CD 4 T细胞帮助的CD 8 T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.