Inefficient cross-presentation limits the CD8+ T cell response to a subdominant tumor antigen epitope

J Immunol. 2005 Jul 15;175(2):700-12. doi: 10.4049/jimmunol.175.2.700.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 2
  • ATP-Binding Cassette Transporters / genetics
  • Adoptive Transfer
  • Animals
  • Antigens, Viral, Tumor / administration & dosage
  • Antigens, Viral, Tumor / biosynthesis
  • Antigens, Viral, Tumor / genetics
  • Antigens, Viral, Tumor / immunology*
  • Antigens, Viral, Tumor / metabolism
  • CD8-Positive T-Lymphocytes / immunology*
  • CD8-Positive T-Lymphocytes / metabolism
  • CD8-Positive T-Lymphocytes / transplantation
  • Cell Line, Transformed
  • Cell Proliferation
  • Clone Cells
  • Cross-Priming / immunology*
  • Cytotoxicity, Immunologic / genetics
  • Epitopes, T-Lymphocyte / administration & dosage
  • Epitopes, T-Lymphocyte / genetics
  • Epitopes, T-Lymphocyte / immunology*
  • Epitopes, T-Lymphocyte / metabolism
  • Immunization, Secondary
  • Immunodominant Epitopes / administration & dosage
  • Immunodominant Epitopes / genetics
  • Immunodominant Epitopes / immunology*
  • Immunodominant Epitopes / metabolism
  • Immunologic Memory / immunology
  • Lymphocyte Activation / genetics
  • Lymphocyte Activation / immunology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Peptide Fragments / immunology
  • Resting Phase, Cell Cycle / genetics
  • Resting Phase, Cell Cycle / immunology
  • Simian virus 40 / immunology
  • T-Lymphocyte Subsets / cytology
  • T-Lymphocyte Subsets / immunology
  • T-Lymphocyte Subsets / metabolism
  • Viral Core Proteins / immunology

Substances

  • ATP Binding Cassette Transporter, Subfamily B, Member 2
  • ATP-Binding Cassette Transporters
  • Antigens, Viral, Tumor
  • Epitopes, T-Lymphocyte
  • Immunodominant Epitopes
  • Peptide Fragments
  • Tap1 protein, mouse
  • Viral Core Proteins
  • nucleoprotein (366-374), influenza virus