The discovery of regulatory T cells (Tregs) is a breakthrough in immunology: it revolutionises our understanding of autoimmune disease (AID) pathophysiology and treatment opportunities. Treg numbers or function is defective in most mouse and human AIDs and their restoration induces clinical improvement, as we recently showed using low-dose IL-2 to induce Tregs in patients with AID.The TRiPoD project is based on 3 well supported assertions:- Tregs have huge therapeutic potential- Deep understanding of the Treg T cell receptor (TCR) repertoire is key to exploiting this potential- Deep sequencing technologies required for this purpose have come of ageTRiPoD aims (i) to decipher the Treg repertoire against insulin and myelin at high resolution, (ii) to discover biomarkers for AIDs, and (iii) to develop therapies based on engineered Tregs.Deep sequencing of TCRs from insulin- and myelin-specific Tregs generated in vitro will identify dominant TCRs and antigen-specific Treg signatures. These will be analysed during thymocyte differentiation, at steady state and during disease progression, in mice and humans. Their potential as biomarkers (e.g. a Treg TCR specific for insulin for monitoring type 1 diabetes [T1D]) will be tested in experimental models and in clinical trials of IL-2 in T1D and multiple sclerosis (MS).We will also generate antigen-specific Tregs expressing the dominant TCRs and investigate their therapeutic properties.Ultimately, TRiPoD will contribute to a better understanding of the pathophysiology of T1D and MS, identify novel biomarkers for the follow-up of patients at high risk of, or with T1D or MS, and generate novel therapeutics for clinical development.More generally, our results and new approaches developed in TRiPoD should pioneer biomarker discovery and biotherapies in other immunopathologies.