CD4 T cells control development and maintenance of brain-resident CD8 T cells during polyomavirus infection

Tissue-resident memory CD8 T (TRM) cells defend against microbial reinfections at mucosal barriers; determinants driving durable TRM cell responses in non-mucosal tissues, which often harbor opportunistic persistent pathogens, are unknown. JC polyomavirus (JCPyV) is a ubiquitous constituent of the human virome. With altered immunological status, JCPyV can cause the oft-fatal brain demyelinating disease progressive multifocal leukoencephalopathy (PML). JCPyV is a human-only pathogen. Using the mouse polyomavirus (MuPyV) encephalitis model, we demonstrate that CD4 T cells regulate development of functional antiviral brain-resident CD8 T cells (bTRM) and renders their maintenance refractory to systemic CD8 T cell depletion. Acquired CD4 T cell deficiency, modeled by delaying systemic CD4 T cell depletion until MuPyV-specific CD8 T cells have infiltrated the brain, impacted the stability of CD8 bTRM, impaired their effector response to reinfection, and rendered their maintenance dependent on circulating CD8 T cells. This dependence of CD8 bTRM differentiation on CD4 T cells was found to extend to encephalitis caused by vesicular stomatitis virus. Together, these findings reveal an intimate association between CD4 T cells and homeostasis of functional bTRM to CNS viral infection.

组织驻留记忆CD8 T细胞（Tissue-resident memory CD8 T cells, TRM）可在黏膜屏障部位抵御微生物再次感染；目前对于驱动非黏膜组织中持久TRM细胞应答的调控因子仍不明晰，而非黏膜组织往往会潜伏伺机致病的持续性病原体。JC多瘤病毒（JC polyomavirus, JCPyV）是人类病毒组中普遍存在的组成成分。当机体免疫状态发生改变时，JC多瘤病毒可引发致死率极高的脑脱髓鞘疾病——进行性多灶性白质脑病（progressive multifocal leukoencephalopathy, PML）。JC多瘤病毒是一种人类专属病原体。本研究利用小鼠多瘤病毒（mouse polyomavirus, MuPyV）脑炎模型证实，CD4 T细胞可调控功能性抗病毒脑驻留CD8 T细胞（brain-resident CD8 T cells, bTRM）的发育，并使其存活不受系统性CD8 T细胞耗竭的影响。若在多瘤病毒特异性CD8 T细胞浸润大脑后，通过延迟系统性CD4 T细胞耗竭来模拟获得性CD4 T细胞缺陷，则会破坏CD8 bTRM的稳定性，削弱其对再次感染的效应应答，并使其存活依赖于循环CD8 T细胞。进一步研究发现，CD8 bTRM分化对CD4 T细胞的这种依赖同样适用于水疱性口炎病毒（vesicular stomatitis virus）引发的脑炎。综上，本研究结果揭示了CD4 T细胞与中枢神经系统（CNS）病毒感染后功能性bTRM的稳态维持之间存在密切关联。