CTL AVIDITY AND THE AGING IMMUNE RESPONSE

这项建议是由一位新的研究人员针对PAR-98-021研究目标第25号-疫苗和免疫反应提出的。尽管拟议的实验不涉及人体临床研究，但结果将对改进老年人疫苗设计以及与年龄相关的免疫反应下降的潜在机制产生直接影响。这项提案中的研究是我在博士后期间所做工作的延伸，现在我自己的实验室试图了解CTL亲和力在免疫反应中的作用。我之前的数据明确地表明，CTL亲和力在清除体内病毒感染方面发挥着重要作用，因为只有高亲和力的CTL才能减少病毒负担。我发现高亲和力、中亲和力或低亲和力的CTL是幼鼠对痘苗病毒免疫反应的正常部分。此外，这些CTL可以在体外扩增，扩增的CTL的功能表型与冲击APC的抗原浓度有关。相比之下，我们一直无法扩大高亲和力的CTL，这是从老年小鼠(20个月)的细胞溶解时，以同样的方式处理。因此，在老年小鼠中，高亲和力CTL的生成似乎存在缺陷。高亲和力反应的优先丧失可能至少在一定程度上导致在老年动物中观察到的流感病毒清除减少。这项建议中描述的研究将确定高亲和力CTL缺陷的程度，例如，是否1)不存在高亲和力CTL，或者2)它们是否被激活，但只有选定的效应器功能存在。这些实验的结果应该成为提交R01资金申请的基础，该申请旨在研究老年小鼠高亲和力CTL选择性缺陷的机制。

This proposal is from a new investigator in response to PAR-98- 021 research objective number 25- Vaccines and immune response. Although the proposed experiments do not involve human clinical studies, the results will have direct implications for the improved design of vaccines for aged people and the underlying mechanism of the age-related decline in the immune response. The studies in this proposal are an extension of the work that I did during my post-doctoral fellowship and now in my own laboratory which seeks to understand the role of CTL avidity in the immune response. My previous data have shown unequivocally an important role for CTL avidity in the clearance of viral infections in vivo as only high avidity CTL were capable of reducing viral burdens. I have found that CTL with high, intermediate, or low avidity are elicited as a normal part of the immune reponse to vaccinia virus in young mice. Further, these CTL can be expanded in vitro and the functional phenotype of CTL that are expanded is related to the antigen concentration with which the APC were pulsed. In contrast, we have been unable to expand high avidity CTL that are cytolytic from aged mice (20 months) when treated in the same way. Thus there appears to be a defect in the generation of high avidity CTL in aged mice. The preferential loss of the high avidity response could be responsible, at least in part, for the reduced clearance of influenza virus observed in aged animals. The studies described in this proposal will define the extent of the deficiency in high avidity CTL, e.g. whether 1) no high avidity CTL are present or 2) whether they are activated but only select effector functions are present. The results from these experiments should form the foundation for the submission of an application for R01 funding investigating the mechanisms responsible for the selective deficiency in high avidity CTL in aged mice.