Inefficient cross-presentation limits the CD8+ T cell response to a subdominant tumor antigen epitope.
CD8(+) T lymphocytes (T(CD8)) responding to subdominant epitopes provide alternate targets for the immunotherapy of cancer, particularly when self-tolerance limits the response to immunodominant epitopes. However, the mechanisms that promote T(CD8) subdominance to tumor Ags remain obscure. We investigated the basis for the lack of priming against a subdominant tumor epitope following immunization of C57BL/6 (B6) mice with SV40 large tumor Ag (T Ag)-transformed cells. Immunization of B6 mice with wild-type T Ag-transformed cells primes T(CD8) specific for three immunodominant T Ag epitopes (epitopes I, II/III, and IV) but fails to induce T(CD8) specific for the subdominant T Ag epitope V. Using adoptively transferred T(CD8) from epitope V-specific TCR transgenic mice and immunization with T Ag-transformed cells, we demonstrate that the subdominant epitope V is weakly cross-presented relative to immunodominant epitopes derived from the same protein Ag. Priming of naive epitope V-specific TCR transgenic T(CD8) in B6 mice required cross-presentation by host APC. However, robust expansion of these T(CD8) required additional direct presentation of the subdominant epitope by T Ag-transformed cells and was only significant following immunization with T Ag-expressing cells lacking the immunodominant epitopes. These results indicate that limited cross-presentation coupled with competition by immunodominant epitope-specific T(CD8) contributes to the subdominant nature of a tumor-specific epitope. This finding has implications for vaccination strategies targeting T(CD8) responses to cancer.
Department of Microbiology and Immunology, Pennsylvania State University College of Medicine, 500 University Drive, Hershey, PA 17033, USA.
Pavel
P
Otahal
Sandra C
SC
Hutchinson
Lawrence M
LM
Mylin
M Judith
MJ
Tevethia
Satvir S
SS
Tevethia
Todd D
TD
Schell
D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D019264:Adoptive Transfer; D000818:Animals; D000957:Antigens, Viral, Tumor / Q000008:administration & dosage / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000637:transplantation; D002461:Cell Line, Transformed; D049109:Cell Proliferation; D002999:Clone Cells; D045142:Cross-Priming / Q000276:immunology*; D003602:Cytotoxicity, Immunologic / Q000235:genetics; D018984:Epitopes, T-Lymphocyte / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D007117:Immunization, Secondary; D016056:Immunodominant Epitopes / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D007156:Immunologic Memory / Q000276:immunology; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010446:Peptide Fragments / Q000276:immunology; D016192:Resting Phase, Cell Cycle / Q000235:genetics / Q000276:immunology; D013539:Simian virus 40 / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D014758:Viral Core Proteins / Q000276:immunology
D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2; D018528:ATP-Binding Cassette Transporters; D000957:Antigens, Viral, Tumor; D018984:Epitopes, T-Lymphocyte; D016056:Immunodominant Epitopes; D010446:Peptide Fragments; C486171:Tap1 protein, mouse; D014758:Viral Core Proteins; C102366:nucleoprotein (366-374), influenza virus