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In this study, we show that IFN-alpha beta can have a direct role in linking innate and adaptive responses by providing the "third signal" needed by naive CD8 T cells responding to Ag and costimulatory ligands. Stimulation of CD8 T cells in the absence of a third signal leads to proliferation, but clonal expansion is limited by poor survival and effector functions do not develop. We show that IFN-alpha beta can provide the third signal directly to CD8 T cells via a STAT4-dependent pathway to stimulate survival, development of cytolytic function, and production of IFN-gamma. Provision of the third signal by either IFN-alpha beta or IL-12 results in regulation of the expression of a number of genes, including several that encode proteins critical for effector function.

Cutting Edge: Type I IFNs Provide a Third Signal to CD8 T Cells to Stimulate Clonal Expansion and Differentiation