CTL AVIDITY AND THE AGING IMMUNE RESPONSE

这是一位新研究者针对PAR-98- 021研究目标25-疫苗和免疫反应提出的建议。虽然拟议的实验不涉及人体临床研究，但其结果将对改进老年人疫苗的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的工作的延伸，现在在我自己的实验室里，我试图了解CTL贪婪在免疫反应中的作用。我以前的数据已经明确地表明CTL贪婪在清除体内病毒感染中的重要作用，因为只有高贪婪的CTL能够减少病毒负担。我发现，在幼鼠对牛痘病毒的免疫反应中，高、中、低活性的CTL都是正常的。此外，这些CTL可以在体外扩增，扩增的CTL的功能表型与APC被脉冲的抗原浓度有关。相反，在同样的处理方法下，我们无法从老年小鼠（20个月）中扩增出高亲和力的细胞溶解性CTL。因此，在老年小鼠中，高贪婪CTL的产生似乎存在缺陷。在老年动物中观察到的流感病毒清除率降低，至少在一定程度上可能是高活动性反应优先丧失的原因。本提案中描述的研究将定义高亲和性CTL缺陷的程度，例如，是否1)不存在高亲和性CTL，或2)它们是否被激活，但只存在特定的效应功能。这些实验的结果应该成为提交R01基金申请的基础，以研究老年小鼠高贪婪性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.