Accumulation of CD28 null CD8+ T cells and the defects of these cells in response to antigenic stimulation are the hallmarks of age-associated decline of T cell function. However, the mechanism of these age-associated changes is not fully understood. In this study, we report an analysis of the growth of human CD28 null and CD28+ CD8+ memory T cells in response to homeostatic cytokine IL-15 in vitro. We showed that 1) there was no proliferative defect of CD28 null CD8+ memory T cells in response to IL-15 compared with their CD28+ counterparts; 2) stable loss of CD28 expression occurred in those actively dividing CD28+ CD8+ memory T cells responding to IL-15; 3) the loss of CD28 was in part mediated by TNF-α that was induced by IL-15; and 4) CCL4 (MIP-1β), also induced by IL-15, had a significant inhibitory effect on the growth of CD28 null cells, which in turn down-regulated their expression of CCL4 receptor CCR5. Together, these findings demonstrate that CD28 null CD8+ memory T cells proliferate normally in response to IL-15 and that IL-15 and its induced cytokines regulate the generation and growth of CD28 null CD8+ T cells, suggesting a possible role of IL-15 in the increase in CD28 null CD8+ T cells that occurs with aging.