OX40 costimulation turns off Foxp3+ Tregs.

OX40 is a recently identified T-cell costimulatory molecule that belongs to the TNF/TNFR superfamily. OX40 can be expressed by both activated T effector cells and Foxp3(+) Tregs. It is well known that OX40 delivers a potent costimulatory signal to T effector cells, but very little is known about the role of OX40 in regulating the suppressor properties of Foxp3(+) Tregs and the de novo generation of new inducible Foxp3(+) Tregs from T effector cells. In the present study, we found, by using a newly created foxp3gfp knockin model, that OX40 was dispensable for the genesis and suppressor functions of naturally arising CD4(+)Foxp3(+) Tregs, but stimulating OX40 on the Foxp3(+) Tregs abrogated their ability to suppress T effector cell proliferation, IFN-gamma production, and T effector cell-mediated allograft rejection. OX40 costimulation did not significantly affect proliferation and survival of the naturally arising Foxp3(+) Tregs, but profoundly inhibited Foxp3 gene expression. Importantly, OX40 costimulation to T effector cells prevented the induction of new inducible Foxp3(+) Tregs from T effector cells. Our study identified OX40 as a key negative regulator of Foxp3(+) Tregs and may have important clinical implications in models of transplantation and autoimmunity.