Chemokine-Guided CD4+ T Cell Help Enhances Generation of IL-6RαhighIL-7Rαhigh Prememory CD8+ T Cells

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Abstract
CD4+ T cells promote effective CD8+ T cell-mediated immunity, but the timing and mechanistic details of such help remain controversial. Furthermore, the extent to which innate stimuli act independently of help in enhancing CD8+ T cell responses is also unresolved. Using a noninfectious vaccine model in immunocompetent mice, we show that even in the presence of innate stimuli, CD4+ T cell help early after priming is required for generating an optimal pool of functional memory CD8+ T cells. CD4+ T cell help increased the size of a previously unreported population of IL-6RαhighIL-7Rαhigh prememory CD8+ T cells shortly after priming that showed a survival advantage in vivo and contributed to the majority of functional memory CD8+ T cells after the contraction phase. In accord with our recent demonstration of chemokine-guided recruitment of naive CD8+ T cells to sites of CD4+ T cell-dendritic cell interactions, the generation of IL-6RαhighIL-7Rαhigh prememory as well as functional memory CD8+ T cells depended on the early postvaccination action of the inflammatory chemokines CCL3 and CCL4. Together, these findings support a model of CD8+ T cell memory cell differentiation involving the delivery of key signals early in the priming process based on chemokine-guided attraction of naive CD8+ T cells to sites of Ag-driven interactions between TLR-activated dendritic cells and CD4+ T cells. They also reveal that elevated IL-6Rα expression by a subset of CD8+ T cells represents an early imprint of CD4+ T cell helper function that actively contributes to the survival of activated CD8+ T cells.