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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.

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IMMUNOBIOLOGY

Negative thymocyte selection to HERV-K18 superantigens in humans

Françoise Meylan, Magda De Smedt, Georges Leclercq, Jean Plum, Olivier Leupin, Samuel Marguerat, and Bernard Conrad

From the Departments of Genetic Medicine and Development and of Genetics and Microbiology, University of Geneva Medical School, Switzerland; and the Department of Clinical Chemistry, Microbiology, and Immunology, Ghent University Hospital, Belgium.

An experimental system to explore central tolerance in humans is unavailable. However, the human endogenous retrovirus K-18 (HERV-K18) region on chromosome 1 provides an excellent model: HERV-K18 encodes a superantigen (SAg) stimulating V{beta}7CD4 T cells that is implicated in type 1 diabetes and Epstein-Barr virus persistence. In this study, we have addressed thymic HERV-K18 SAg expression, the capacity of SAg to induce negative selection, and the consequences of this for peripheral tolerance compared with SAg reactivity. We demonstrate that thymic HERV-K18 SAg expression is constitutive and is 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 antigen-presenting cells (APCs). Using this assay, the HERV-K18 SAg is necessary and sufficient for negative selection of immature or semimature V{beta}7CD4 thymocytes. Decreases of SAg reactive V{beta}7CD4 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 compared with SAg reactivity. This study now offers a framework to dissect negative selection and its interplay with viral persistence and autoimmunity in humans.


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