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Blood, 1 June 2005, Vol. 105, No. 11, pp. 4377-4382. Prepublished online as a Blood First Edition Paper on January 11, 2005; DOI 10.1182/blood-2004-07-2596. This Article Full Text (PDF) Supplemental Figures All Versions of this Article: 2004-07-2596v1 105/11/4377    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Meylan, F. Articles by Conrad, B. Search for Related Content PubMed PubMed Citation Articles by Meylan, F. Articles by Conrad, B. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted July 12, 2004 Accepted December 18, 2004 Negative thymocyte selection to HERV-K18 superantigens in humans Francoise Meylan, Magda De Smedt, Georges Leclercq, Jean Plum, Olivier Leupin, Samuel Marguerat, and Bernard Conrad* Departments of Genetics & Microbiology, University of Geneva Medical School, Geneva, Switzerland Department of Clinical Chemistry, Microbiology and Immunology, Ghent University Hospital, Ghent, Switzerland Departments of Genetic Medicine & Development, University of Geneva Medical School, Geneva, Switzerland Departments of Genetic Medicine & Development, University of Geneva Medical School, Geneva, Switzerland; Departments of Genetics & Microbiology, University of Geneva Medical School, Geneva, Switzerland * Corresponding author; email: bernard.conrad{at}medecine.unige.ch. An experimental system to explore central tolerance in humans is currently not available. However, the human endogenous retrovirus (HERV)-K18 region on chromosome 1 provides an excellent model: HERV-K18 encodes a superantigen (SAg) stimulating V7CD4 T cells that is implicated in type 1 diabetes and Epstein-Barr virus persistence. In this manuscript, we have addressed thymic HERV-K18 SAg expression, the capacity of the SAg to induce negative selection, and the consequences of this for peripheral tolerance versus SAg reactivity. We demonstrate that thymic HERV-K18 SAg expression is constitutive, and restricted in time and space such that it can induce negative selection. We developed an in vitro assay capable of detecting negative human thymocyte selection by bacterial SAgs presented on extrathymic APCs. Using this assay, the HERV-K18 SAg is necessary and sufficient for negative selection of immature or semimature V7CD4 thymocytes. Decreases of SAg reactive V7CD4 T cells generated in the thymus predict low or absent SAg reactivity. Therefore, these results indicate that negative thymic selection to HERV-K18 SAgs constitutes a first checkpoint controlling peripheral tolerance versus SAg reactivity. This work now offers a framework to dissect negative selection, and its interplay with viral persistence and autoimmunity in humans. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: G. G. M. Doxiadis, N. de Groot, and R. E. Bontrop Impact of Endogenous Intronic Retroviruses on Major Histocompatibility Complex Class II Diversity and Stability J. Virol., July 1, 2008; 82(13): 6667 - 6677. [Abstract] [Full Text] [PDF] G. Rajagopalan, M. Singh, M. M. Sen, N. S. Murali, K. A. Nath, and C. S. David Endogenous Superantigens Shape Response to Exogenous Superantigens Clin. Vaccine Immunol., September 1, 2005; 12(9): 1119 - 1122. [Abstract] [Full Text] [PDF]

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