T Cell Help Amplifies Innate Signals in CD8+ DCs for Optimal CD8+ T Cell Priming

DCs often require stimulation from CD4+ T cells to propagate CD8+ T cell responses, but precisely how T cell help optimizes the priming capacity of DCs and why this appears to differ between varying types of CD8+ T cell immunity remains unclear. We show that CD8+ T cell priming upon HSV-1 skin infection depended on DCs receiving stimulation from both IFN-α/β and CD4+ T cells to provide IL-15. This was not an additive effect but resulted from CD4+ T cells amplifying DC production of IL-15 in response to IFN-α/β. We also observed that increased innate stimulation reversed the helper dependence of CD8+ T cell priming and that the innate stimulus, rather than the CD4+ T cells themselves, determined how “help’” was integrated into the priming response by DCs. These findings identify T cell help as a flexible means to amplify varying suboptimal innate signals in DCs. [Display omitted] •IFN-α/β and CD4+ T cells cooperate in enabling CD8+ DCs to provide IL-15•Innate circuit stimulation determines cytokine requirements of CTL priming•T cell help for CD8+ T cell priming is a means to amplify innate circuits in DCs Greyer et al. show that “T cell help” optimizes CD8+ T cell priming by amplifying innate signals in DCs, illustrating that the innate circuits stimulated during priming and not the CD4+ T cells, dictate how T cell help is integrated into CD8+ T cell priming.