Type I IFN (IFN-αβ), which is produced rapidly in response to infection, plays a key role in innate immunity and also acts as a stimulus for the adaptive immune response. We have investigated how IFN-αβ induces cross-priming, comparing CD8+ T cell responses generated against soluble protein Ags in the presence or absence of IFN-αβ. Injection of IFN-α was found to prolong the proliferation and expansion of Ag-specific CD8+ T cells, which was associated with marked up-regulation of IL-2 and IL-15 receptors on Ag-specific cells and expression of IL-15 in the draining lymph node. Surprisingly, neither IL-2 nor IL-15 was required for IFN-α-induced cross-priming. Conversely, expression of the IFN-αβR by T cells was shown to be necessary for effective stimulation of the response by IFN-α. The finding that T cells represent direct targets of IFN-αβ-mediated stimulation reveals an additional mechanism by which the innate response to infection promotes adaptive immunity.