 In NOD mice with type 1 diabetes, T1D, a progressive decline in FOXP3 plus regulatory T, TREG, cell function leads to autoimmunity which is rescued by prophylactic Illinois 2 therapy. Islet infiltrating TREG cells express the inducible T-cell co-stimulator, ICOS, and have enhanced fitness and suppressive function, but KLRG1 plus ICOS plus TREG cells are prone to apoptosis and have impaired proliferative capacity and suppressive function. The global pool of FOXP3 plus TREG cells displays some functional plasticity in vivo, but the KLRG1 plus ICOS plus TREG cell subset is particularly susceptible to lose FOXP3 expression and reprogram into TH1, or TH17, like effector T, TEF, cells. This article was authored by Mara Cornet, Edward Mason, Roman Istamin, and others.