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TCR Down-Regulation Controls Virus-Specific CD8⁺ T Cell Responses¹

Charlotte Menné Bonefeld^*, Mariëlle Haks^2,, Bodil Nielsen^*, Marina von Essen^*, Lasse Boding^*, Ann Kathrine Hansen^*, Jeppe Madura Larsen^*, Niels Ødum^*, Paul Krimpenfort, Ada Kruisbeek^3,, Jan Pravsgaard Christensen^*, Allan Randrup Thomsen^* and Carsten Geisler^4,*

^* Department of International Health, Immunology and Microbiology, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark and The Netherlands Cancer Institute, Amsterdam, The Netherlands

The CD3 di-leucine-based motif plays a central role in TCR down-regulation. However, little is understood about the role of the CD3 di-leucine-based motif in physiological T cell responses. In this study, we show that the expansion in numbers of virus-specific CD8⁺ T cells is impaired in mice with a mutated CD3 di-leucine-based motif. The CD3 mutation did not impair early TCR signaling, nor did it compromise recruitment or proliferation of virus-specific T cells, but it increased the apoptosis rate of the activated T cells by increasing down-regulation of the antiapoptotic molecule Bcl-2. This resulted in a 2-fold reduction in the clonal expansion of virus-specific CD8⁺ T cells during the acute phase of vesicular stomatitis virus and lymphocytic choriomeningitis virus infections. These results identify an important role of CD3-mediated TCR down-regulation in virus-specific CD8⁺ T cell responses.

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 by grants from The Danish Medical Research Council, The Novo Nordisk Foundation, The A.P. Møller Foundation for the Advancement of Medical Sciences, The Agnes and Poul Friis Foundation, and The Astrid Thaysen Foundation for Basic Medical Sciences.

² Current address: Leiden University Medical Center, Department of Immunohematology and Blood Transfusion, Leiden, The Netherlands.

³ Current address: VUmc Cancer Center Amsterdam, PO Box 7057 MB, Amsterdam, The Netherlands.

⁴ Address correspondence and reprint requests to Dr. Carsten Geisler, Department of International Health, Immunology and Microbiology, Faculty of Health Sciences, University of Copenhagen, Blegdamsvej 3C, Copenhagen, Denmark. E-mail address: cge{at}sund.ku.dk

⁵ Abbreviations used in this paper: diL, di-leucine-based; PTK, protein tyrosine kinase; PKC, protein kinase C; KO, knock-out; WT, wild type; LN, lymph node; VSV, vesicular stomatitis virus; LCMV, lymphocytic choriomeningitis virus; MFI, mean fluorescence intensity; PDB, phorbol 12,13-dibutyrate; LAT, linker for activation of T cells.

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				L. Boding, C. M. Bonefeld, B. L. Nielsen, J. P. H. Lauritsen, M. R. von Essen, A. K. Hansen, J. M. Larsen, M. M. Nielsen, N. Odum, and C. Geisler TCR Down-Regulation Controls T Cell Homeostasis J. Immunol., October 15, 2009; 183(8): 4994 - 5005. [Abstract] [Full Text] [PDF]