An alternative signal 3: CD8⁺ T cell memory independent of IL-12 and type I IFN is dependent on CD27/OX40 signaling.

Type I IFN and IL-12 are well documented to serve as so called "signal 3" cytokines, capable of facilitating CD8(+) T cell proliferation, effector function and memory formation. While their ability to serve in this capacity is well established, to date, no non-cytokine signal 3 mediators have been clearly identified. We have established a vaccine model system in which the primary CD8(+) T cell response is independent of either IL-12 or type I IFN receptors, but dependent on CD27/CD70 interactions. We show here that primary and secondary CD8(+) T cell responses are generated in the combined deficiency of IFN and IL-12 signaling. In contrast, antigen specific CD8(+) T cell responses are compromised in the absence of the TNF receptors CD27 and OX40. These data indicate that CD27/OX40 can serve the central function as signal 3 mediators, independent of IFN or IL-12, for the generation of CD8(+) T cell immune memory.