Toll样受体配体直接激活老龄化CD8 T细胞的抗流感佐剂功能

Circulation of influenza viruses causes regional and global outbreaks in human populations and results in million infection cases with associated influences on world economics. During influenza outbreak, in particular, the old population has shown high morbidity and mortality. Due to dramatic decrease of the T cell immune responses, the seasonal influenza vaccination is unable to provide adequate protection in aged people. Also, the loss of T cell adaptive immunity exacerbates the disease severity in infected aged population. A decline in output of na?ve CD8 T cells is observed with increasing age, while the proportion of memory CD8 T cells is relatively increased due to a lifetime exposure to the various pathogens. These memory CD8 T cells, however, compromise immune function with associated loss of costimulation molecules after progressive exhaustion. Therefore, it is crucial to characterize the immunosenescent CD8 T cells and increase their immune responses against influenza infection. In this study, the characterization of na?ve and memory CD8 T cells in the aged human population will be studied, in particular, the expression paradigm of toll-like receptor (TLR) on these cell types will be illustrated. Given that TLR agonists are capable of directly enhancing immune responses of the normal CD8 T cells, the capability of multiple TLR agonists for restoring the immunity of human immunosenescent CD8 T cells will be investigated. Additionally, anti-influenza immunity of the murine immunosenescent CD8 T cells stimulated with the TLR agonists will be studied in both ex vivo and in vivo. The results of both human and animal studies are aiming to better understand the role that TLR signaling play in improving immunosenescence of CD8 T cells and, provide valuable information for designing vaccine adjuvant and developing therapeutic strategy to enhance CD8 T cell responses against influenza.

随着老龄化发展，天然CD8 T细胞数量巨减，并且记忆CD8 T细胞的免疫功能出现紊乱。这使得流感疫苗对老年人的免疫保护率下降，同时也导致该人群在感染过程中不能有效控制疾病症状。因此，揭示老龄化CD8 T细胞免疫学特性以及如何提高其抗流感的免疫功能将是一个很有意义的课题。本课题拟从该点入手，研究人的老龄化天然、记忆CD8 T细胞的免疫特性，并对该两类细胞表达Toll样受体（TLR）的特点进行说明。因TLR配体可直接激活正常CD8 T细胞，本课题将着重考察通过TLR配体刺激以恢复人的老龄化CD8 T细胞免疫效力的潜力。另外通过对小鼠老龄化CD8 T细胞免疫特性和TLR表达特点的比较研究，以及对该类细胞经TLR配体刺激后在体外和体内抗流感免疫效力的分析，以期更全面地认识TLR信号通路提升老龄化CD8 T细胞抵御流感的协同作用。本研究将为T细胞疫苗佐剂的设计和抗流感T细胞靶向治疗提供理论依据。

随着老龄化发展，天然CD8T细胞数量巨减，并且记忆CD8T细胞的免疫功能出现紊乱。这使得疫苗对老年人的免疫保护率下降，同时也导致该人群在感染过程中不能有效控制疾病症状。针对该问题，本课题对人的老龄化T细胞的亚类表型进行了分析，发现了老年人与年轻人之间CD8T细胞的亚群组成差异，其中老年人记忆CD8T细胞（EM和CM）数量显著升高，较记忆CD4T细胞的数量变化更为明显。另外，课题组证实了老龄化CD8T细胞的协同信号分子CD28的表达水平显著下降，通过CD28抗体刺激无法激活记忆CD8T细胞应答。为了明确老龄化记忆CD8T细胞是否具有其他的协同激活通路，课题组对记忆CD8T细胞中TLR的表达水平进行了分析，发现TLR家族基因在老年人记忆CD8T细胞中的表达特点，特别是发现TLR1/3/6/9在老龄化记忆CD8T细胞中呈现高表达。随后课题组在体外对多种TLR配体直接激活记忆CD8T细胞的协同刺激功能进行了考察，发现TLR1/2配体与CD3单抗可在体外激活老龄化记忆CD8T细胞的增殖，其激活效应与CD28的协同激活效应类似。另外，课题组亦在小鼠中对老龄化T细胞的组成及TLR的协同激活作用进行了考察，发现了类似的实验结果。本课题的研究成果发现了TLR通路可作为激活老龄化记忆CD8T细胞的协同激活信号，具有协同激活分子CD28的类似免疫功能，预示其可作为疫苗佐剂激活老龄化记忆CD8T细胞的免疫应答。