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Elevated Frequencies of Self-reactive CD8⁺ T Cells following Immunization with a Xenoantigen Are Due to the Presence of a Heteroclitic CD4⁺ T-Cell Helper Epitope

¹ Center for Gene Therapeutics, Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada and ² Swiss Institute for Experimental Cancer Research, Lausanne, Switzerland

Requests for reprints: Jonathan Bramson, Department of Pathology and Molecular Medicine, McMaster University, Room MDCL-5025, 1200 Main Street West, Hamilton, Ontario, Canada L8N 3Z5. Phone: 905-525-9140; Fax: 905-522-6750; E-mail: bramsonj{at}mcmaster.ca.

Immunization of mice with human dopachrome tautomerase (hDCT) provides greater protection against melanoma than immunization with the murine homologue (mDCT). We mapped the CD8⁺ and CD4⁺ T-cell epitopes in both proteins to better understand the mechanisms of the enhanced protection. The dominant CD8⁺ T-cell epitopes were fully conserved between both proteins, yet immunization with hDCT produced frequencies of CD8⁺ T cells that were 5- to 10-fold higher than immunization with mDCT. This difference was not intrinsic to the two proteins because comparable frequencies of CD8⁺ T cells were elicited by both antigens in DCT-deficient mice. Strikingly, only hDCT elicited a significant level of specific CD4⁺ T cells in wild-type (WT) mice. The murine protein was not devoid of CD4⁺ T-cell epitopes because immunization of DCT-deficient mice with mDCT resulted in robust CD4⁺ T-cell immunity directed against two epitopes that were not identified in WT mice. These results suggested that the reduced immunogenicity of mDCT in WT mice may be a function of insufficient CD4⁺ T-cell help. To address this possibility, the dominant CD4⁺ T-cell epitope from hDCT was introduced into mDCT. Immunization with the mutated mDCT evoked CD8⁺ T-cell frequencies and protective immunity comparable with hDCT. These results reveal a novel mechanism by which xenoantigens overcome tolerance. Our data also suggest that immunologic tolerance is more stringent for CD4⁺ T cells than CD8⁺ T cells, providing a mechanism of peripheral tolerance where autoreactive CD8⁺ T cells fail to be activated due to a lack of autoreactive CD4⁺ T cells specific for the same antigen. [Cancer Res 2007;67(13):6459–67]

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