title: OX40 costimulation turns off Foxp3+ Tregs.
abstract: 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.
authors.affiliation: Harvard Medical School, Transplant Research Center, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA.
authors.forename: Minh Diem
authors.initials: MD
authors.lastname: Vu
authors.forename: Xiang
authors.initials: X
authors.lastname: Xiao
authors.forename: Wenda
authors.initials: W
authors.lastname: Gao
authors.forename: Nicolas
authors.initials: N
authors.lastname: Degauque
authors.forename: Ming
authors.initials: M
authors.lastname: Chen
authors.forename: Alexander
authors.initials: A
authors.lastname: Kroemer
authors.forename: Nigel
authors.initials: N
authors.lastname: Killeen
authors.forename: Naoto
authors.initials: N
authors.lastname: Ishii
authors.forename: Xian Chang
authors.initials: XC
authors.lastname: Li
mesh_terms: D000818:Animals; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D007371:Interferon-gamma / Q000096:biosynthesis; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D053262:Receptors, OX40 / Q000276:immunology* / Q000378:metabolism*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism*
chemical_list: D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D053262:Receptors, OX40; C505717:Tnfrsf4 protein, mouse; D007371:Interferon-gamma