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Blood, 1 October 2007, Vol. 110, No. 7, pp. 2501-2510. Prepublished online as a Blood First Edition Paper on June 15, 2007; DOI 10.1182/blood-2007-01-070748.
IMMUNOBIOLOGY OX40 costimulation turns off Foxp3+ Tregs1 Harvard Medical School, Transplant Research Center, Beth Israel Deaconess Medical Center, Boston, MA; 2 Department of Microbiology and Immunology, University of California San Francisco; 3 Department of Microbiology and Immunology, Tohoku University Graduate School of Medicine, Sendai, Japan
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-
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| Copyright © 2007 by American Society of Hematology Online ISSN: 1528-0020 | |||||||||||
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. 
