With aging, substantial changes occur in both the functional and phenotypic profiles of T cells in humans and rodents. Among the functional changes that occur in the aged are alterations in the profile of cytokines produced, changes in the early events of signal transduction and decreased cellular proliferation in response to TCR- and costimulus- mediated stimulation. Among the phenotypic changes is a dramatic shift toward an increased proportion of memory cells with a concomitant decline in the proportion of naive cells. Although many of the age-associated functional changes are proposed to be the consequence of this population shift, superimposed on this are likely to be intrinsic changes in function. Using TCR transgenic mouse models we will address the following issues: 1) Is the shift to a memory phenotype in the aged due to antigenic stimulation?; 2) Which alterations associated with the "aged phenotype" are attributable to the aging process vs. the shift to memory cell predominance?; 3) Since exposure to environmental antigens occurs throughout one's lifetime, what effect does repeated exposures to antigen have on responsiveness?; 4) Of those cells switched to a memory phenotype, can they respond to antigen as well as those from the young? (i.e., Is the proportion of antigen-specific memory cells capable of responding decreased with age? Is the frequency of antigen-responsive cells decreased? On a per cell basis, is the average level of responsiveness decreased?); 5) Which processes of memory T cell responsiveness in the aged are altered (i.e., Is there a decline in the generation of CTL and CD4 effectors? Is there a decline in CTL or CD4 responsiveness?); 6) Can we elucidate any mechanism(s) involved in the age-associated alterations (i.e., Are there any age-associated alterations in cytokine production and receptor expression, fas and P-glycoprotein expression, etc.)?; 7) The same questions may be addressed to the small population of naive cells that are found in the aged. Answers to these simple yet important questions will affect strategies for vaccinating the elderly.