In the elderly, a dramatic shift within the CD4+ T cell population occurs, with an increased proportion having a memory phenotype with markedly decreased responsiveness. To determine what aspects of the aged phenotype are dependent upon repeated contact with antigen in the environment, we examined CD4+ cells isolated from TCR Tg mice. There is good evidence that no cross-reacting antigens for the Tg TCR recognizing pigeon cytochrome c are found in the environment of the animal, so that alterations in the Tg CD4+ cells with aging are likely to be due to antigen-independent processes. We found that in aged animals, TCR transgene(pos) CD4+ cells, although decreased in number and antigen responsiveness, maintain a naive phenotype rather than acquiring a prototypical aged memory phenotype. In contrast, the population of transgene(1o-neg) CD4+ cells increase in proportion and express the aged phenotype. Consistent with their naive status, transgene(pos) cells of aged individuals remain CD44lo CD45RBhi, secrete IL-2 and not IL-4 or IFN-gamma upon antigenic stimulation, and require co-stimulation to proliferate to anti-CD3 stimulation. These findings suggest that the aging-associated shift to CD4 cells expressing the memory phenotype is dependent on antigenic stimulation. However, the decrease in antigen responsiveness of naive transgenepos cells, as revealed by a lower secretion of IL-2 and IL-3 and a lower proliferative capacity, suggests that additional intrinsic changes occur with aging that do not depend on encounter with antigen.