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Cognate Memory CD4⁺ T Cells Generated with Dendritic Cell Priming Influence the Expansion, Trafficking, and Differentiation of Secondary CD8⁺ T Cells and Enhance Tumor Control¹

Department of Pathology, Human Immune Therapy Center, University of Virginia Health System, Charlottesville, VA 22908

CD4⁺ T cells are known to provide support for the activation and expansion of primary CD8⁺ T cells, their subsequent differentiation, and ultimately their survival as memory cells. However, the importance of cognate memory CD4⁺ T cells in the expansion of memory CD8⁺ T cells after re-exposure to Ag has been not been examined in detail. Using bone marrow-derived dendritic cells pulsed with cognate or noncognate MHC class I- and class II-restricted peptides, we examined whether the presence of memory CD4⁺ T cells with the same Ag specificity as memory CD8⁺ T cells influenced the quantity and quality of the secondary CD8⁺ T cell response. After recombinant vaccinia virus-mediated challenge, we demonstrate that, although cognate memory CD4⁺ T cells are not required for activation of secondary CD8⁺ T cells, their presence enhances the expansion of cognate memory CD8⁺ T cells. Cognate CD4⁺ T cell help results in an approximate 2-fold increase in the frequency of secondary CD8⁺ T cells in secondary lymphoid tissues, and can be accounted for by enhanced proliferation in the secondary CD8⁺ T cell population. In addition, cognate memory CD4⁺ T cells further selectively enhance secondary CD8⁺ T cell infiltration of tumor-associated peripheral tissue, and this is accompanied by increased differentiation into effector phenotype within the secondary CD8⁺ T cell population. The consequence of these improvements to the magnitude and phenotype of the secondary CD8⁺ T cell response is substantial increase in control of tumor outgrowth.

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 National Cancer Institute Howard Temin K01 Award CA-95093 and the Sidney Kimmel Foundation for Cancer Research (both to T.N.J.B.).

² Address correspondence and reprint requests to Dr. Timothy N. J. Bullock, University of Virginia, MR4 Building, Room 2035, Lane Road, Charlottesville, VA 22908. E-mail address: tbullock{at}virginia.edu

³ Abbreviations used in this paper: DC, dendritic cell; BMDC, bone marrow-derived DC; PTLN, paratracheal lymph node; OVA-vac, recombinant vaccinia virus expressing full-length OVA; OVA257-vac, minigene expressing OVA257.

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