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Induction of Tolerance in CD8⁺ T Cells to a Transgenic Autoantigen Expressed in the Liver Does Not Require Cross-Presentation¹

Department of Immunology, School of Medicine, University of Washington, Seattle, WA 98195 and Program in Immunology, Fred Hutchinson Cancer Research Center, Seattle, WA 98109

Cross-presentation of normal self and candidate tumor Ags by bone marrow (BM)-derived APCs that have not been activated has been demonstrated as a major mechanism contributing to acquisition of tolerance by mature T cells that first encounter an Ag in the periphery (cross-tolerance). Following adoptive transfer of naive TCR-transgenic CD8⁺ T cells into a host expressing a transgenic Ag that is a potentially targetable tumor Ag in normal hepatocytes as a self-Ag, we found that the majority of Ag-specific CD8⁺ T cells were deleted, with the remaining cells rendered anergic. Studies in BM chimeric mice and with purified cell populations demonstrated that these events were not dependent on cross-presentation by BM-derived APCs including Kupffer cells or liver sinusoidal endothelial cells, and apparently can occur entirely as a consequence of direct recognition of Ag endogenously processed and presented by hepatocytes. Direct recognition of Ag-expressing hepatocytes in vivo induced a proliferative response and up-regulation of activation markers in responding CD8⁺ T cells, but proliferating cells did not accumulate, with most cells rapidly eliminated, and the persisting T cells lost the capacity to proliferate in response to repeated Ag stimulation. The results suggest that parenchymal tissues may retain the capacity to directly regulate in vivo responses to self-Ags processed and presented in the context of class I MHC molecules.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported in part by Grants CA33084 and CA18029 from the U.S. National Institutes of Health/National Cancer Institute and by a grant from the Leukemia and Lymphoma Society.

² Address correspondence and reprint requests to Dr. Philip D. Greenberg, Department of Immunology, School of Medicine, University of Washington, and Fred Hutchinson Cancer Research Center, Box 356527, 1959 NE Pacific Street, Seattle, WA 98195. E-mail address: pgreen{at}u.washington.edu

³ Abbreviations used in this paper: BM, bone marrow; Tg, transgenic; LN, lymph node; LCMV, lymphocytic choriomeningitis virus; LSEC, liver sinusoidal endothelial cell; FMuLV, Friend murine leukemia virus; ALT, alanine aminotransferase; PD, programmed death.

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				E. D. Reynoso and S. J. Turley Unconventional antigen-presenting cells in the induction of peripheral CD8+ T cell tolerance J. Leukoc. Biol., October 1, 2009; 86(4): 795 - 801. [Abstract] [Full Text] [PDF]