Negative thymocyte selection to HERV-K18 superantigens in humans

Abstract

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␤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␤7CD4 thymocytes. Decreases of SAg reactive V␤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. IntroductionSelf-tolerance is a multistage process progressively established during T-cell development in the thymus and maintained in the periphery throughout the lifespan of mature T cells. Much of the initial concepts of T-cell tolerance emerged from studying the biology of superantigens (SAgs) in mice. 1,2 SAgs stimulate 10 3 to 10 5 more T cells than do conventional antigens, a feature that is based on their capacity to selectively bind V␤ chains on T cells in a variety of different modes indiscriminately and without regard for their antigen specificity. 3 Infectious and endogenous mouse mammary tumor viruses (MMTVs) encode several SAgs with different T-cell receptor (TCR) V␤ specificities. 4,5 Multiple forms of T-cell tolerance develop to these SAgs; negative selection in the thymus is one of the most extensively studied. It results in partial or complete deletion of mature T cells expressing SAg-reactive V␤ chains from the peripheral repertoire. 6 Thymic deletion reflects the susceptibility of immature and semimature thymocytes to undergo negative selection at the corticomedullary junction and in the thymic medulla replete of professional antigen-presenting cells (APCs). 7,8 It requires that SAg expression exceed a threshold level during thymocyte development 9,10 and that SAgs be presented by the appropriate thymic cell type, which includes medullary epithelial cells and hematopoietic APCs. 11 Expression of some MMTV SAgs is restricted to the thymocyte lingeage, 12 and efficient deletion in these instance relies on paracrine transfer to major histocompatibility complex (MHC) class 2 ϩ thymic APCs. 13,14 SAg-induced central tolerance, therefore, depends...

Impact of Endogenous Intronic Retroviruses on Major Histocompatibility Complex Class II Diversity and Stability

“…Furthermore, the presence or absence of HERVs may influence whether a particular host is susceptible/resistant to incoming exogenous retroviruses and to autoimmune diseases. An example is provided by the HERV-W envelope protein syncetin-1, which is highly ex-pressed in glia cells of the central nervous system in multiple sclerosis patients (3,34,57). Additionally, multiple sclerosis susceptibility/resistance is affected by specific trans-located DR genes/gene products (60).…”

Perinatal Immunotoxicity: Why Adult Exposure Assessment Fails to Predict Risk

“…This occurs during the process sometimes designated as “T-cell education.” Meylan et al (2005) provided a clear demonstration of this process as it occurs in humans. Partially mature thymocytes undergo negative selection at the corticomedullary boundary and in the medulla of thymus (Sprent and Kishimoto 2002).…”

Is Autoimmunity a Component of Natural Immunity to HIV?

“…Priming of naïve mice with SAg-expressing cells first induces the activation of T cells expressing a specific V-beta TCR chain, followed by T cell tolerance and polyclonal B cell activation, leading to IgM and IgG production [107]. Experiments carried out in a mouse model of autoimmune disease, the pre-diabetic NOD mouse, have shown that IFN-alpha expression, following a viral infection, induces the expression of a SAg encoded by the polymorphic family of HERV-K18 endogenous retroviruses [106]. Expression of SAg can be therefore mediated by inflammatory stimuli, such as IFNalpha, and this finding provides a link between inflammation and viral infections, suggesting a possible mechanism for autoimmunity onset [153].…”

“…ERV also carry SAg-encoding sequences, able to induce non-specific lymphocytes activation and desensitisation [5,106]. Various evidences indeed support the occurrence of ERV-mediated autoimmunity, at least in some animal or human populations displaying a "permissive" immune repertoire [153].…”

“…Superantigens (SAg) from bacteria or viruses are known to induce rapid, polyclonal T and B activation, followed by anergy and/or lymphocyte depletion. In fact, ERV-encoded SAgs are expressed in the thymus and take part to negative selection of reactive T cell clones, through the intervention of professional APC, such as dendritic cells and B lymphocytes [5,106]. Priming of naïve mice with SAg-expressing cells first induces the activation of T cells expressing a specific V-beta TCR chain, followed by T cell tolerance and polyclonal B cell activation, leading to IgM and IgG production [107].…”