The Journal of Experimental Medicine
Janeway's Immunobiology 7th Edition
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Published online 28 May 2002 doi:10.1084/jem.20011063
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© Rockefeller University Press, 0022-1007/2002/6/1407/ $5.00
The Journal of Experimental Medicine, Volume 195, Number 11, June 3, 2002 1407-1418
CD8+ T Cell Tolerance to a Tumor-associated Antigen Is Maintained at the Level of Expansion Rather than Effector Function

Claes Öhlén1, Michael Kalos1, Laurence E. Cheng1, Aaron C. Shur2, Doley J. Hong2, Bryan D. Carson1, Niels C.T. Kokot1, Cara G. Lerner1, Blythe D. Sather1, Eric S. Huseby1 and Philip D. Greenberg1,3

1 Department of Immunology, University of Washington, Seattle, WA 98195
2 Department of Medicine/Division of Oncology, University of Washington, Seattle, WA 98195
3 Fred 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: ohlen{at}u.washington.edu

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 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.

Key Words: CTL • hepatocyte • tumor immunology • autoimmunity • signaling


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