Data from 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

Abstract

<div>Abstract<p>Immunization of mice with human dopachrome tautomerase (hDCT) provides greater protection against melanoma than immunization with the murine homologue (mDCT). We mapped the CD8<sup>+</sup> and CD4<sup>+</sup> T-cell epitopes in both proteins to better understand the mechanisms of the enhanced protection. The dominant CD8<sup>+</sup> T-cell epitopes were fully conserved between both proteins, yet immunization with hDCT produced frequencies of CD8<sup>+</sup> 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<sup>+</sup> T cells were elicited by both antigens in DCT-deficient mice. Strikingly, only hDCT elicited a significant level of specific CD4<sup>+</sup> T cells in wild-type (WT) mice. The murine protein was not devoid of CD4<sup>+</sup> T-cell epitopes because immunization of DCT-deficient mice with mDCT resulted in robust CD4<sup>+</sup> 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<sup>+</sup> T-cell help. To address this possibility, the dominant CD4<sup>+</sup> T-cell epitope from hDCT was introduced into mDCT. Immunization with the mutated mDCT evoked CD8<sup>+</sup> 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<sup>+</sup> T cells than CD8<sup>+</sup> T cells, providing a mechanism of peripheral tolerance where autoreactive CD8<sup>+</sup> T cells fail to be activated due to a lack of autoreactive CD4<sup>+</sup> T cells specific for the same antigen. [Cancer Res 2007;67(13):6459–67]</p></div>