Defective MHC class II presentation by dendritic cells limits CD4 T cell help for antitumor CD8 T cell responses.
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 CD8alpha+ 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 CD8alpha+ DC and helping tolerized CD8 T cells.
Center for Immunology, University of Minnesota, Minneapolis, MN 55455, USA.
Michael Y
MY
Gerner
Kerry A
KA
Casey
Matthew F
MF
Mescher
D000818:Animals; D000941:Antigens / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D045744:Cell Line, Tumor; D003593:Cytoplasm / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology*; D000949:Histocompatibility Antigens Class II / Q000276:immunology*; D008198:Lymph Nodes / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000276:immunology* / Q000473:pathology; D010047:Ovalbumin / Q000276:immunology / Q000378:metabolism
D000941:Antigens; D000949:Histocompatibility Antigens Class II; D010047:Ovalbumin