OX40 costimulation turns off Foxp3+ Tregs

MD Vu, X Xiao, W Gao, N Degauque… - Blood, The Journal …, 2007 - ashpublications.org
MD Vu, X Xiao, W Gao, N Degauque, M Chen, A Kroemer, N Killeen, N Ishii, X Chang Li
Blood, The Journal of the American Society of Hematology, 2007ashpublications.org
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 …
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-γ 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.
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