| First Author | Hassler T | Year | 2020 |
| Journal | Ludwig-Maximilians-University Munich | Mgi Jnum | J:323554 |
| Mgi Id | MGI:7263347 | Citation | Hassler T (2020) How central tolerance shapes the polyclonal CD4 T cell repertoire specific for the central nervous system antigen myelin proteolipid protein 1. Ludwig-Maximilians-University Munich |
| abstractText | The fate of a developing T cell is dependent on the interaction of its T cell receptor (TCR) and the self-peptide MHC complex on thymic antigen presenting cells. According to the classical affinity/avidity model of thymocyte selection, the degree of auto- reactivity determines if potentially harmful T cells are diverted into regulatory T cells (intermediate affinity/avidity) or clonally deleted (high affinity/avidity). Nevertheless, how central tolerance induction to a physiological self-antigen is set in the polyclonal repertoire is still poorly understood. In the presented thesis, we are focusing on the naturally-expressed tissue-restricted antigen myelin proteolipid protein 1 (PLP1), the main component of the myelin sheath, as it is discussed to be one of the putative target antigens in multiple sclerosis (MS) in humans. Upon PLP1 immunization, non-tolerant murine strains develop experimental autoimmune encephalomyelitis (EAE), a MS-like disease, whereas C57BL/6 mice are resistant to EAE and lack recall responses, due to the expression of PLP1 in thymic epithelial cells. Klein et al. previously showed that, upon immunization of PLP1-deficient C57BL/6 mice, CD4 T cells react to three epitopes within the PLP1 protein (PLP111-19, PLP1174-182 and PLP1240-248) [1]. To further investigate the mechanisms of central tolerance induction to PLP1, we generated two PLP1:I-Ab tetramers to follow the destiny of PLP111-19 and PLP1240-248-specific T cells in the polyclonal CD4 compartment. Initially, we identified regulatory T cell induction upon self-recognition as the dominant tolerance mechanism for both PLP111-19 and PLP1240-248-specific T cells. We then focused on endogenous PLP111-19-specific CD4 T cells and we detected differences between the T cell repertoires of PLP1-deficient and PLP1-sufficient C57BL/6 mice, with regard to abundance and Treg cell induction. Furthermore, we could describe in more detail to which extent TRA critical factors such as AIRE, mTECs and also DCs influence the tolerance processes and we collected evidence for T cell anergy induction as a third alternative pathway to tolerize PLP1 specific T cells in the thymus. Finally, single cell sequencing of tolerant and naïve PLP111-19-specific TCR repertoires uncovered TCR candidates that were deleted, whereas others underwent diversion into the Treg cell lineage upon antigen encounter. The characterization of selected TCRs in TCR transgenic mice partially favors the (affinity)/avidity model, although one PLP1- specific TCR does not fit into the model and leaves space for an alternative interpretation of thymocyte selection rules. |
