Immunological Tolerance – AG Ludger Klein

Negative selection versus induction of regulatory 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).

Positive selection and the generation of a ‘useful’ T cell repertoire

Positive selection requires permissive interactions with a single antigen presenting cell (APC) type, namely cortical thymic epithelial cells (cTECs). Why positive selection depends on a single stromal cell type remains a conundrum, but it is becoming increasingly clear that the crucial role of cTECs is, at least in part, specified by unique machineries that these cells use to generate pMHC ligands. These proteolytic pathways are likely to endow cTECs with an at least in part ‘private’ self-peptide/major histocompatibility complex (pMHC) ligandome different from that on other APCs. In this context, we are addressing how the cTEC specific protease Cathepsin L shapes the CD4 T cell repertoire and imprints the functional competence of mature T cells.

DFG: SFB 1054 Control and Plasticity of Cell-Fate Decisions in the Immune System
Project A01: Determinants of Intrathymic T Cell Fate Decisions: the Role of Thymic B Cells

ERC AdG742290: ERC-Advanced Grant "TOLERANCE FOOTPRINT"

DFG: LK1228/8-1 The role of cathepsin L in shaping a functional CD4 T cell repertoire

European Union H2020 Integrated Training Network (ITN) ENLIGHT-TEN+, ESR 3: Understanding determinants of T cell fate decisions through repertoire analyses
Web-link: http://www.enlight-ten.eu/