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The Journal of Immunology, 1998, 161: 1718-1727.
Copyright © 1998 by The American Association of Immunologists

Receptor-Specific Allelic Exclusion of TCRV{alpha}-Chains During Development

Richard Boyd*, Ivona Kozieradzki{dagger}, Ann Chidgey*, Hans-Willi Mittrücker{dagger}, Dennis Bouchard{dagger}, Emma Timms{dagger}, Kenji Kishihara{dagger}, Christopher J. Ong{ddagger}, Daniel Chui{ddagger}, Jamey D. Marth§, Tak W. Mak{dagger} and Josef M. Penninger1,{dagger}

* Department of Pathology and Immunology, Monash Medical School, Melbourne, Victoria, Australia; {dagger} Amgen Institute, Ontario Cancer Institute, and Departments of Medical Biophysics and Immunology, University of Toronto, Ontario, Canada; {ddagger} The Biomedical Research Centre and Departments of Medical Genetics and Biochemistry, University of British Columbia, Vancouver, Canada; and § Howard Hughes Medical Institute, Division of Cellular and Molecular Medicine, University of California at San Diego, La Jolla, CA 92093

Expression of a single Ag receptor on lymphocytes is maintained via allelic exclusion that generates cells with a clonal receptor repertoire. We show in normal mice and mice expressing functionally rearranged TCR{alpha}ß transgenes that allelic exclusion at the TCR{alpha} locus is not operational in immature thymocytes, whereas most mature T cells express a single TCRV{alpha}-chain. TCRV{alpha} allelic exclusion in mature thymocytes is regulated through a CD45 tyrosine phosphatase-mediated signal during positive selection. Using functional and genetic systems for selection of immature double TCRV{alpha}+ thymocytes, we show that peptide-specific ligand recognition provides the signal for allelic exclusion, i.e., mature T cells maintain expression of the ligand-specific TCRV{alpha}-chain, but lose the nonfunctional receptor. Whereas activation of TCRVß-chains or CD3{epsilon} leads to receptor internalization, TCRV{alpha} ligation promotes retention of the TCR on the cell surface. Although both TCRV{alpha}- and TCRVß-chains trigger phosphotyrosine signaling, only the TCRVß-chain mediates membrane recruitment of the GTPase dynamin. These data indicate that TCRV{alpha}-directed signals for positive selection control allelic exclusion in T cells, and that developmental signals can select for single receptor usage.




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