Molecular basis for the generation of a self-tolerant TCR repertoire

Project Summary

The thymus supports T cell development through the provision of a dedicated stromal environment, whose function depends on the presence of a single transcription factor, FOXN1. A transgenic mouse line has been developed, in which the mouse Foxn1 gene is replaced by its homologue from the cephalochordate amphioxus. In these mice, T-cell development stalls at the CD4/CD8 double-positive stage, with only few CD4 and CD8 cells appearing in the thymus and the periphery; the seemingly incomplete intrathymic selection processes cause a complex autoimmune syndrome, chiefly characterized by inflammatory bowel disease and vitiligo. Using this mouse model, and a second line expressing Foxn1 homologues from sharks, which lacks autoimmune features, this project aims at identifying the key parameters determining thymic tolerance induction by comparative cytological and molecular analyses.