Negative Selection versus Induction of Suppressor T cells
It is well established that encounter of self-antigen during intrathymic development can lead to the “suicide” of potentially dangerous, autoreactive T cells. However, some T cells with specificity for self-antigens are spared from deletion and instead differentiate into so-called regulatory T cells. The parameters that influence the choice between these mechanisms of tolerance are not understood. One of our goals is to elucidate the developmental cues (stromal interaction partner, signal strength, maturation state) that control this developmental decision.
“Promiscuous” expression of self-antigens in the thymus
Deletion or re-programming of T cells upon encounter of self-antigens during intrathymic development is a cornerstone of immunological self-tolerance. We found that the range of self-antigens expressed in the thymus is unexpectedly broad. This so called “promiscuous” intrathymic expression of otherwise strictly tissue-specific proteins is confined to a particular cell type, medullary epithelial cells. We aim to elucidate the mechanistic basis for this phenomenon (e.g. specific induction versus de-repression of particular genes) and the consequences for particular T cell specificities (deletion versus induction of anergy/regulatory function).
Generation of MHC/peptide ligands for T cell repertoire selection
MHC / peptide (MHCp) complexes on thymic epithelial cells are critical for the generation of a self-MHC restricted and tolerant T cell repertoire. However, these cells exhibit a conspicuous inefficiency of the “classical” MHC II loading pathway. Several “non-classical” MHC II loading pathways have recently been characterized in vitro. We are addressing their potential role for T cell tolerance and repertoire selection in vivo.