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Chemokine-Guided CD4⁺ T Cell Help Enhances Generation of IL-6R^highIL-7R^high Prememory CD8⁺ T Cells¹

Lymphocyte Biology Section, Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892

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-6R^highIL-7R^high 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-6R^highIL-7R^high 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-6R 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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health.

² Address correspondence and reprint requests to Dr. Ronald N. Germain, Lymphocyte Biology Section, Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Building 10, Room 11N-311, 10 Center Drive, Bethesda, MD 20892-1892. E-mail address: rgermain{at}nih.gov

³ Abbreviations used in this paper: TH, T cell help; DC, dendritic cell; KO, knockout; LN, lymph node.

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