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Stimulating naïve CD8 +  T cells with specific antigens and costimulatory signals is insufficient to induce optimal clonal expansion and effector functions. In this study, we show that the activation and differentiation of CD8 +  T cells require IL-2 provided by activated CD4 +  T cells at the initial priming stage within 0–2.5 hours after stimulation. This critical IL-2 signal from CD4 +  cells is mediated through the IL-2Rβγ of CD8 +  cells, which is independent of IL-2Rα. The activation of IL-2 signaling advances the restriction point of the cell cycle, and thereby expedites the entry of antigen-stimulated CD8 +  T-cell into the S phase. Besides promoting cell proliferation, IL-2 stimulation increases the amount of IFNγ and granzyme B produced by CD8 +  T cells. Furthermore, IL-2 at priming enhances the ability of P14 effector cells generated by antigen activation to eradicate B16.gp33 tumors  in vivo . Therefore, our studies demonstrate that a full CD8 +  T-cell response is elicited by a critical temporal function of IL-2 released from CD4 +  T cells, providing mechanistic insights into the regulation of CD8 +  T cell activation and differentiation.

CD4+ T Cell-Derived IL-2 Signals during Early Priming Advances Primary CD8+ T Cell Responses