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Defective MHC Class II Presentation by Dendritic Cells Limits CD4 T Cell Help for Antitumor CD8 T Cell Responses¹

Center for Immunology, University of Minnesota, Minneapolis, MN 55455

Cancer immunosurveillance failure is largely attributed to insufficient activation signals and dominant inhibitory stimuli for tumor Ag (TAg)-specific CD8 T cells. CD4 T cells have been shown to license dendritic cells (DC), thereby having the potential for converting CD8 T cell responses from tolerance to activation. To understand the potential cooperation of TAg-specific CD4 and CD8 T cells, we have characterized the responses of naive TCR transgenic CD8 and CD4 T cells to poorly immunogenic murine tumors. We found that whereas CD8 T cells sensed TAg and were tolerized, the CD4 T cells remained ignorant throughout tumor growth and did not provide help. This disparity in responses was due to normal TAg MHC class I cross-presentation by immature CD8⁺ DC in the draining lymph node, but poor MHC class II presentation on all DC subsets due to selective inhibition by the tumor microenvironment. Thus, these results reveal a novel mechanism of cancer immunosubversion, in which inhibition of MHC-II TAg presentation on DC prevents CD4 T cell priming, thereby blocking any potential for licensing CD8⁺ DC and helping tolerized 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 National Institutes of Health Grants AI34824 (to M.F.M.), CA82596 (to M.F.M.), and NCI 2 T32 CA009138-31 (to M.Y.G.).

² Address correspondence and reprint requests to Dr. Matthew F. Mescher, Lab, Medicine and Pathology, Mayo Mail Code 334, 420 Delaware Street SE, Minneapolis, MN 55455. E-mail address: mesch001{at}umn.edu

³ Abbreviations used in this paper: DC, dendritic cell; DLN, draining lymph node; GrzB, granzyme B; i.t., intratumoral; LN, lymph node; MFI, mean fluorescence intensity; TAg, tumor Ag; TIDC, tumor-infiltrating DC; Treg, T regulatory.