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

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.