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 γ. This split tolerance was accompanied by inhibition of Ca2+ flux, ERK1/2, and Jun kinasephosphorylation, 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.
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3 June 2002
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May 28 2002
CD8+ T Cell Tolerance to a Tumor-associated Antigen Is Maintained at the Level of Expansion Rather than Effector Function
Claes Öhlén,
Claes Öhlén
1Department of Immunology, University of Washington, Seattle, WA 98195
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Michael Kalos,
Michael Kalos
1Department of Immunology, University of Washington, Seattle, WA 98195
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Laurence E. Cheng,
Laurence E. Cheng
1Department of Immunology, University of Washington, Seattle, WA 98195
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Aaron C. Shur,
Aaron C. Shur
2Department of Medicine/Division of Oncology, University of Washington, Seattle, WA 98195
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Doley J. Hong,
Doley J. Hong
2Department of Medicine/Division of Oncology, University of Washington, Seattle, WA 98195
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Bryan D. Carson,
Bryan D. Carson
1Department of Immunology, University of Washington, Seattle, WA 98195
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Niels C.T. Kokot,
Niels C.T. Kokot
1Department of Immunology, University of Washington, Seattle, WA 98195
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Cara G. Lerner,
Cara G. Lerner
1Department of Immunology, University of Washington, Seattle, WA 98195
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Blythe D. Sather,
Blythe D. Sather
1Department of Immunology, University of Washington, Seattle, WA 98195
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Eric S. Huseby,
Eric S. Huseby
1Department of Immunology, University of Washington, Seattle, WA 98195
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Philip D. Greenberg
Philip D. Greenberg
1Department of Immunology, University of Washington, Seattle, WA 98195
3Fred Hutchinson Cancer Research Center, Seattle, WA 98109
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Claes Öhlén
1Department of Immunology, University of Washington, Seattle, WA 98195
Michael Kalos
1Department of Immunology, University of Washington, Seattle, WA 98195
Laurence E. Cheng
1Department of Immunology, University of Washington, Seattle, WA 98195
Aaron C. Shur
2Department of Medicine/Division of Oncology, University of Washington, Seattle, WA 98195
Doley J. Hong
2Department of Medicine/Division of Oncology, University of Washington, Seattle, WA 98195
Bryan D. Carson
1Department of Immunology, University of Washington, Seattle, WA 98195
Niels C.T. Kokot
1Department of Immunology, University of Washington, Seattle, WA 98195
Cara G. Lerner
1Department of Immunology, University of Washington, Seattle, WA 98195
Blythe D. Sather
1Department of Immunology, University of Washington, Seattle, WA 98195
Eric S. Huseby
1Department of Immunology, University of Washington, Seattle, WA 98195
Philip D. Greenberg
1Department of Immunology, University of Washington, Seattle, WA 98195
3Fred Hutchinson Cancer Research Center, Seattle, WA 98109
Address correspondence to Claes Öhlén, Dept. of Immunology, Box 356527, University of Washington, Seattle, WA 98195. Phone: 206-616-8504; Fax: 206-685-3128; E-mail: [email protected]
M. Kalos's present address is Corixa Corporation, 1124 Columbia St., Seattle, WA 98104.
E.S. Huseby's present address is HHMI, National Jewish Medical and Research Center, 1400 Jackson St., Denver, CO 80206.
*
Abbreviations used in this paper: JNK, Jun kinase; TAA, tumor-associated antigen.
Received:
June 20 2001
Revision Received:
February 20 2002
Accepted:
April 12 2002
Online ISSN: 1540-9538
Print ISSN: 0022-1007
The Rockefeller University Press
2002
J Exp Med (2002) 195 (11): 1407–1418.
Article history
Received:
June 20 2001
Revision Received:
February 20 2002
Accepted:
April 12 2002
Citation
Claes Öhlén, Michael Kalos, Laurence E. Cheng, Aaron C. Shur, Doley J. Hong, Bryan D. Carson, Niels C.T. Kokot, Cara G. Lerner, Blythe D. Sather, Eric S. Huseby, Philip D. Greenberg; CD8+ T Cell Tolerance to a Tumor-associated Antigen Is Maintained at the Level of Expansion Rather than Effector Function . J Exp Med 3 June 2002; 195 (11): 1407–1418. doi: https://doi.org/10.1084/jem.20011063
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