Negative thymocyte selection to HERV-K18 superantigens in humans.
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 Vbeta7CD4 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 Vbeta7CD4 thymocytes. Decreases of SAg reactive Vbeta7CD4 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.
Meylan
Françoise
F
Department of Genetic Medicine and Development, University of Geneva Medical School, CH-1211 Geneva 4, Switzerland.
De Smedt
Magda
M
Leclercq
Georges
G
Plum
Jean
J
Leupin
Olivier
O
Marguerat
Samuel
S
Conrad
Bernard
B
D000328:Adult; D000368:Aged; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002648:Child; D002878:Chromosomes, Human, Pair 1; D020077:Endogenous Retroviruses; D016368:Frameshift Mutation; D005786:Gene Expression Regulation / Q000276:immunology; D006801:Humans; D007108:Immune Tolerance; D008565:Membrane Proteins / Q000276:immunology*; D008875:Middle Aged; D016297:Mutagenesis, Site-Directed; D012191:Retroviridae Proteins / Q000235:genetics / Q000276:immunology*; D018089:Superantigens / Q000276:immunology*; D013950:Thymus Gland / Q000166:cytology* / Q000276:immunology; D014162:Transfection
C107453:ERVK-18 protein, human; D008565:Membrane Proteins; D012191:Retroviridae Proteins; D018089:Superantigens