Research
Promiscuous gene expression and T cell tolerance
Figure 1
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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 few percent of T cells survive.
The Division of Developmental Immunology mainly focuses on cellular and molecular mechanisms regulating central tolerance in experimental models of 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 large array of TRAs, a phenomenon termed “promiscuous gene expression” (pGE). Our division focuses on the following aspects of this topic: I) Characterization of pGE in mice and humans at the mRNA level by gene arrays and at the 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 Myasthenia gravis) and in tumor immunity. Our research on self-tolerance encompasses basic and translational aspects.
