病毒特异性记忆性CD4+ T 细胞抗寨卡病毒感染的保护作用机制研究

Zika virus (ZIKV) is an emerging mosquito-borne flavivirus that can cause severe disease in humans, including microcephaly in neonates and Guillain-Barré syndrome (GBS) in adults. There is no effective vaccine and drugs developed against ZIKV infection. Memory T cells and memory B cells could protect from virus reinfection. The important role of CD4+ T cells is to mediate the innate and adapted immune responses. To date, our research indicated that memory CD4+ T cells would protect from ZIKV infection, and most importantly the protection mechanisms are not well understood. In this study, the role of ZIKV specific memory CD4+ T cells against ZIKV infection will be investigated. The phenotypes, functions and kinetics of virus-specific T cells derived from memory CD4+ T cells, and the influence on innate and CD8+ T cell and humoral immune responses, the role of CD4+ T cells secreted will be studied systematically. This study will not only be useful to extend our understanding of ZIKV induced immune response, but also will contribute ZIKV vaccine design, prevention and control of ZIKV disease in China.

寨卡病毒（Zika virus，ZIKV）感染可引起新生儿小头畸形和成人格林巴利综合征等严重神经系统损伤。目前，尚没有有效疫苗和治疗药物。感染或疫苗免疫诱导产生的病毒特异性记忆性CD4+ T细胞在调节固有及适应性免疫应答中发挥关键作用。我们前期研究证实，疫苗免疫产生ZIKV特异性记忆性CD4+ T细胞可保护小鼠免受致死剂量ZIKV的感染，但保护机制仍不清楚。本项目将采用流式细胞术结合ZIKV小鼠脑炎和睾丸损伤动物模型，系统阐明ZIKV记忆性CD4+ T细胞表型及功能，及其对固有免疫、CD8+ T细胞应答和体液免疫的影响，解析病毒特异性CD4+ T细胞杀伤靶细胞功能及其分泌的IFN-γ在抗ZIKV免疫中的保护作用。本项目从分子、细胞和动物水平，全面解析病毒特异性记忆性CD4+ T细胞对ZIKV感染免疫保护的作用机制，为ZIKV感染免疫致病机制的阐明及疫苗研发提供理论依据。

寨卡病毒（Zika virus，ZIKV）感染可引起新生儿小头畸形和成人格林巴利综合征等严重神经系统损伤。目前，尚没有有效疫苗和治疗药物。感染或疫苗免疫诱导产生的病毒特异性记忆性CD4+ T细胞在调节固有及适应性免疫应答中发挥关键作用。本研究发现ZIKV特异性效应性及记忆性CD4+ T细胞可保护小鼠免受致死剂量ZIKV的感染并减轻睾丸组织损伤。进一步研究阐明ZIKV特异性记忆性CD4+ T细胞可通过多种途径发挥保护作用：1) 记忆性CD4+ T细胞对抗原肽的亲和力增强、可快速增殖并迁移至感染部位；2) CD4+ T细胞具有直接杀伤靶细胞作用；3) 在感染早期，记忆性CD4+ T细胞可增强CD8+ T细胞向感染部位的迁移；4) CD40L可促进和调节CD4+ T细胞应答；5) CD4+ T细胞可分泌IFN-γ，促进CD4+ T细胞应答，同时增强下游ISG的表达，发挥抗病毒作用。ZIKV特异性记忆性CD4+ T细胞可能通过以上机制发挥免疫调节及抗病毒作用。本研究首次从分子、细胞和动物水平，全面解析病毒特异性记忆性CD4+ T细胞对ZIKV感染免疫保护的作用机制，为ZIKV感染免疫机制研究及疫苗开发提供理论依据。