title: CD8(+) T cell tolerance to a tumor-associated antigen is maintained at the level of expansion rather than effector function.
abstract: CD8+ T cell tolerance to self-proteins prevents autoimmunity but represents an obstacle to generating T cell responses to tumor-associated antigens. We have made a T cell receptor (TCR) transgenic mouse specific for a tumor antigen and crossed TCR-TG mice to transgenic mice expressing the tumor antigen in hepatocytes (gag-TG). TCRxgag mice showed no signs of autoimmunity despite persistence of high avidity transgenic CD8+ T cells in the periphery. Peripheral CD8+ T cells expressed phenotypic markers consistent with antigen encounter in vivo and had upregulated the antiapoptotic molecule Bcl-2. TCRxgag cells failed to proliferate in response to antigen but demonstrated cytolytic activity and the ability to produce interferon gamma. This split tolerance was accompanied by inhibition of Ca(2+) flux, ERK1/2, and Jun kinase phosphorylation, and a block in both interleukin 2 production and response to exogenous interleukin 2. The data suggest that proliferation and expression of specific effector functions characteristic of reactive cells are not necessarily linked in CD8+ T cell tolerance.
authors.affiliation: Department of Immunology, University of Washington, Seattle, WA 98195, USA. ohlen@u.washington.edu
authors.forename: Claes
authors.initials: C
authors.lastname: Ohlén
authors.forename: Michael
authors.initials: M
authors.lastname: Kalos
authors.forename: Laurence E
authors.initials: LE
authors.lastname: Cheng
authors.forename: Aaron C
authors.initials: AC
authors.lastname: Shur
authors.forename: Doley J
authors.initials: DJ
authors.lastname: Hong
authors.forename: Bryan D
authors.initials: BD
authors.lastname: Carson
authors.forename: Niels C T
authors.initials: NC
authors.lastname: Kokot
authors.forename: Cara G
authors.initials: CG
authors.lastname: Lerner
authors.forename: Blythe D
authors.initials: BD
authors.lastname: Sather
authors.forename: Eric S
authors.initials: ES
authors.lastname: Huseby
authors.forename: Philip D
authors.initials: PD
authors.lastname: Greenberg
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000235:genetics / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology* / Q000276:immunology*; D002118:Calcium / Q000378:metabolism; D002455:Cell Division; D002457:Cell Extracts; D005434:Flow Cytometry; D015870:Gene Expression; D007108:Immune Tolerance / Q000276:immunology*; D007371:Interferon-gamma / Q000378:metabolism; D007376:Interleukin-2 / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases; D051379:Mice; D008822:Mice, Transgenic; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction; D013154:Spleen / Q000166:cytology / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D019014:fas Receptor / Q000378:metabolism; D018631:ras Proteins / Q000378:metabolism
chemical_list: D000951:Antigens, Neoplasm; D002457:Cell Extracts; D007376:Interleukin-2; D019253:Proto-Oncogene Proteins c-bcl-2; D011948:Receptors, Antigen, T-Cell; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor; D007371:Interferon-gamma; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; D018631:ras Proteins; D002118:Calcium