Regulatory T cells (Tregs) are important therapeutic targets for many immunopathologies. Stimulating Tregs with interleukin-2 (IL-2), the key cytokine supporting Treg fitness, is being actively developed, but is likely to be insufficient to achieve optimal therapeutic efficacy in severe diseases. This is why many groups are developing Treg cell-based therapies, harnessing the experience accumulate during the development of CAR T cell therapies for cancer. In this emerging field, we propose to develop an innovation aimed at generating enhanced-Tregs (e.Tregs) by rendering them IL-2 self-sufficient. We have already proven that, compared to control Tregs, e.Tregs expressing a mutated IL-2 (IL-2N88R) that cannot activate Teffs (i) survive much better in IL-2 deprived environments, (ii) are more stable in phenotype and (iii) have a much better therapeutic efficacy. We will complete the preclinical development of e.Tregs and perform a first-in-man dose-escalation phase-I/II study in chronic graft-versus-host-disease (cGVHD).For this purpose, we will (i) finalize the optimal design of the lentiviral vector to be used, including addition of a suicide gene; (ii) optimize the entire process to select, gene-modify and expand Tregs under good manufacturing practices (GMP) and (iii) perform a dose-escalation phase 1/2 study in patients with cGVHD. The partners are experts in stem cell transplantation and cell therapy who have developed their own academic production of CAR T cells for leukaemia, used in more than 400 patients. They will translate their know-how to e.Tregs.We aim to validate a new therapeutic approach for the treatment of cGVHD, a condition with high mortality and morbidity and unmet clinical needs. Furthermore, we expect that our results will motivate researchers to harness the e.Treg technology in their products, notably CAR Tregs.This should have a major impact by enabling more effective therapies for high-burden diseases or disorders with unmet medical needs.