Modulation of CD8+ T cell response to antigen by the levels of self MHC class I.
The response of H-Y-specific TCR-transgenic CD8(+) T cells to Ag is characterized by poor proliferation, cytolytic activity, and IFN-gamma secretion. IFN-gamma secretion, but not cytotoxic function, can be rescued by the B7.1 molecule, suggesting that costimulation can selectively enhance some, but not all, effector CD8(+) T cell responses. Although the H-Y epitope binds H-2D(b) relatively less well than some other epitopes, it can induce potent CTL responses in nontransgenic mice, suggesting that the observed poor responsiveness of transgenic CD8(+) T cells cannot be ascribed to the epitope itself. Previously reported reactivity of this TCR to H-2A(b) is also not the cause of the poor responsiveness of the H-Y-specific CD8(+) T cells, as H-Y-specific CD8(+) T cells obtained from genetic backgrounds lacking H-2A(b) also responded poorly. Rather, reducing the levels of H-2(b) class I molecules by breeding the mice to (C57BL/6 x B10.D2)F(1) or TAP1(+/-) backgrounds partially restored cytotoxic activity and enhanced proliferative responses. These findings demonstrate that the self MHC class I gene dosage may regulate the extent of CD8(+) T cell responsiveness to Ag.
Santori
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Michael Heidelberger Division of Immunology, Department of Pathology, and Kaplan Comprehensive Cancer Center, New York University School of Medicine, New York, NY 10016, USA.
Arsov
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Vukmanović
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D000818:Animals; D000941:Antigens / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D002460:Cell Line; D002461:Cell Line, Transformed; D003602:Cytotoxicity, Immunologic / Q000235:genetics; D018984:Epitopes, T-Lymphocyte / Q000235:genetics; D005260:Female; D006182:H-Y Antigen / Q000235:genetics; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000378:metabolism*; D000949:Histocompatibility Antigens Class II / Q000235:genetics; D056466:Histone Demethylases; D007371:Interferon-gamma / Q000378:metabolism; D008213:Lymphocyte Activation / Q000235:genetics; D008297:Male; D051379:Mice; D008805:Mice, Inbred A; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010446:Peptide Fragments / Q000276:immunology; D011506:Proteins / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000235:genetics; D017634:Self Tolerance / Q000235:genetics; D016176:T-Lymphocyte Subsets / Q000276:immunology; D015778:Minor Histocompatibility Antigens
D000941:Antigens; D018984:Epitopes, T-Lymphocyte; D006182:H-Y Antigen; D015395:Histocompatibility Antigens Class I; D000949:Histocompatibility Antigens Class II; D056466:Histone Demethylases; D007371:Interferon-gamma; D010446:Peptide Fragments; D011506:Proteins; D011948:Receptors, Antigen, T-Cell; C490659:Kdm5d protein, mouse; D015778:Minor Histocompatibility Antigens