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.
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.
Kianizad
Korosh
K
Center for Gene Therapeutics, Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada.
Marshall
Laura A
LA
Grinshtein
Natalie
N
Bernard
Dannie
D
Margl
Renate
R
Cheng
Sheng
S
Beermann
Friedrich
F
Wan
Yonghong
Y
Bramson
Jonathan
J
D000595:Amino Acid Sequence; D000818:Animals; D015478:Antigens, Heterophile / Q000378:metabolism*; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism*; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism*; D000939:Epitopes / Q000737:chemistry; D005260:Female; D007108:Immune Tolerance; D007167:Immunotherapy / Q000379:methods*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D017386:Sequence Homology, Amino Acid; D013601:T-Lymphocytes / Q000378:metabolism
D015478:Antigens, Heterophile; D000939:Epitopes