Immunologic memory is a critical feature of the adaptive immune system to fight recurrent infections. However, the mechanisms that shape the composition and function of the human memory T-cell pool remain incompletely understood. We here demonstrate that post-thymic human T-cell differentiation was associated with the downregulation, but not loss, of the inhibitory molecule CD5. The sensitivity of human CD8 + and CD4 + memory T cells to interleukin (IL)–15 was inversely associated with the level of CD5 expression. CD5 expression was downregulated by IL-15–mediated signaling in vitro and CD5 lo memory T cells accumulated in the bone marrow. Persistent antigenic stimulation, as in the case of cytomegalovirus infection and rheumatoid arthritis (RA), was also associated with an increased number of CD5 lo memory T cells. In conclusion, CD5 may be a useful marker to identify memory T-cell subsets with distinct responsiveness to the homeostatic cytokine IL-15.