Promiscuous gene expression, T cell tolerance and autoimmunity

Figure 1

The immune system is delicately balanced between self-antigen driven tolerance and pathogen-driven immunity. Self-tolerance of the T cell repertoire, which is an essential aspect of this balance, is mediated by multiple mechanisms operating both in the thymus (central tolerance) and in peripheral lymphoid and non-lymphoid organs (peripheral tolerance). The thymus, a primary lymphoid organ, is the site where T lymphocytes develop from bone marrow-derived precursors to maturity. During their development, T cells pass through different thymic microenvironments in a spatially and temporally ordered process (Fig. 1). Along this passage they are endowed with molecules, which enable them to specifically recognize foreign antigens and exert their diverse effector functions. At the same time T cells “learn” to tolerate self-antigens. The acquisition of this ability to discriminate between self and non-self antigens is based on stringent selection events, which only a minor percent of developing T cells survive.

The Division of Developmental Immunology mainly focuses on cellular and molecular mechanisms regulating central tolerance in experimental models, i.e. mice and rats, and in humans. In particular, we study the role of medullary thymic epithelial cells (mTECs) in tolerance towards tissue-restricted self-antigens (TRAs). These epithelial cells have the unusual property of expressing a diverse spectrum of TRAs, a phenomenon termed “promiscuous gene expression” (pGE). Our research covers the following aspects of this topic: I) Characterization of pGE in mice, rat and humans at the transcriptional and protein level in single cells, II) Characterization of the cellular and the molecular regulation of pGE, (III) Presentation of and tolerance induction by TRAs in the thymus. IV) Assessing the role of pGE in the patho-physiology of human autoimmune diseases (as Type 1 Diabetes mellitus) and in tumor immunity. In the context of the developmental biology of thymic epithelial cells, we study thymic epithelial stem cells in mouse and human. Our research on these various topics encompasses both, basic and translational aspects.

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