Regulatory T cells (Tregs) suppress alloimmune reaction such as graft versus host disease (GvHD)1 and promote tolerance induction to allogeneic organ transplants.2 In high-risk acute leukaemia patients undergoing full-haplotype mismatched transplantation we demonstrated that adoptive immunotherapy with Tregs conventional T cells (Tcons) almost completely prevented acute and chronic GvHD, favoured post-transplant immunological reconstitution and was associated with a powerful graft-versus-leukaemia (GvL) effect.3, 4, 5 Interestingly, GvHD severity and mortality was markedly reduced by inactivation of NOTCH signalling in donor T cells by means of humanised antibodies and conditional genetic models.6, 7, 8 The present study attempted to unravel the connection between Tregs and NOTCH signalling in Tcons for GvHD prevention. We discovered that NOTCH1 downregulation on Tcons is a new Treg mechanism of action and showed that Tregs use the CD39 pathway to modulate NOTCH1 expression on Tcons.