Together, these findings describe an immune cascade in which α-GalCer-activated iNKT cells orchestrate the expansion and function of CD8<sup>+</sup> T<sub>VM</sub> cells through IL-4 production, reveal previously unrecognized roles of CD8<sup>+</sup> T<sub>VM</sub> cells as downstream effectors in α-GalCer-mediated immunotherapeutic effects, and highlight the protective potential of CD8<sup>+</sup> T<sub>VM</sub> cells in host defense against diverse pathogens, thus providing a novel approach to developing new therapeutics for combating not only various infectious diseases but also tumors. Here, CD8A is linked to infectious disease.