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.
