Impact of aging on naive CD4 T cell function. We have made substantial progress in understanding age-related defects in naive CD4 T cell function, using murine T cell receptor transgenic (TCR Tg) models. We have found that decreased responsiveness to TCR stimulation in naive T cells from aged animals leads to reduced IL-2 production, proliferation and effector generation both in vitro and in vivo. In addition, memory T cells that are derived from naive CD4 T cells obtained from aged animals exhibit severe defects in proliferation, cytokine production and cognate helper function. It is quite likely that this defect contributes significantly to the reduction in vaccine efficacy observed in the elderly. Our studies have also shown that we can enhance the response of naive CD4 T cells from aged mice in vitro by the addition of exogenous IL-2 and in vivo by the use of adjuvants that induce the production of inflammatory cytokines. We have shown that a combination of these cytokines (TNFalpha, IL-1, IL-6) induces enhanced IL-2 production by aged naive cells by increasing NFKappaB activation. This, in turn, enhances primary effector generation both in vitro and in vivo. These results are exciting since they indicate that these age-related defects may be overcome by the use of adjuvants that induce higher levels of these cytokines. In this current proposal, we will continue our studies using similar experimental models. We hypothesize that the origin of the age-related defect in naive CD4 T cells is due to the fact that they are chronologically older compared to those found in younger animals. If naive T cells are chronologically older, there must be factors which regulate this. In Aim 1, we will examine the factors that may be involved in the regulation of CD4 lifespan, including other lymphocyte populations, thymic output and endogenous cytokines. In Aim 2, we will determine the effects of these age-related defects on the ability of naive CD4 T cells from aged mice to generate functional memory cells. Our overall goal is to determine what factors are involved in the genesis of age-related CD4 T cell defects, how they work, and the impact that they have on the generation of functional memory cells which are involved in protection from infectious disease.