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Summary One of the most prominent changes during T-cell aging in humans is the accumulation of CD28null T cells, mainly CD8+ and also CD4+ T cells. Enhancing the functional properties of these cells may be important as they provide an antigen-specific defense against chronic infections. Recent studies have shown that IL-15 does in fact play an appreciable role in CD4 memory T cells under physiological conditions. We found that treatment with IL-15 increased the frequency of elderly CD4+CD28null T cells by the preferential proliferation of these cells compared to CD4+CD28+ T cells. IL-15 induced an activated phenotype in CD4+CD28null T cells. Although the surface expression of IL-15R α-chain was not increased, the transcription factor STAT-5 was preferentially activated. IL-15 augmented the cytotoxic properties of CD4+CD28null T cells by increasing both the mRNA transcription and storage of granzyme B and perforin for the cytolytic effector functions. Moreover, pretreatment of CD4+CD28null T cells with IL-15 displayed a synergistic effect on the IFN-γ production in CMV-specific responses, which was not observed in CD4+CD28+ T cells. IL-15 could play a role enhancing the effector response of CD4+CD28null T cells against their specific chronic antigens. [ABSTRACT FROM AUTHOR]