Effector memory T cells are effective in controlling acute infections, but central memory T cells play a key role in long-lasting protection against viruses and tumors. In vivo/in vitro challenge by Ag commonly supports the generation of effector memory T cells with limited longevity. To our knowledge, this study demonstrates for the first time in the human system and under rechallenge conditions that targeting IL-2R by partial mammalian target of rapamycin inhibition or blocking IL-2Rα enriches human CD4+/CD8+ central memory T cells within the virus-specific T cell product associated with enhanced functionality (ie, multicytokine secretors, including IL-2; enhanced CD137 and CD107a expression on CD8+ and CD4+ T cells, respectively; and killing infected target cells). Remarkably, the effects on CD8+ T cells are mainly mediated via the enhancement of CD4+ T cell function. The data reveal new insights into the role of CD4+ T cell support for the quality of CD8+ T cell memory, even under rechallenge conditions. Moreover, our method offers a new approach to improve the long-lasting efficacy of adoptive T cell therapy in patients.