title: New insights on OX40 in the control of T cell immunity and immune tolerance in vivo.
abstract: OX40 is a T cell costimulatory molecule that belongs to the TNFR superfamily. In the absence of immune activation, OX40 is selectively expressed by Foxp3(+) regulatory T cells (Tregs), but not by resting conventional T cells. The exact role of OX40 in Treg homeostasis and function remains incompletely defined. In this study, we demonstrate that OX40 engagement in vivo in naive mice induces initial expansion of Foxp3(+) Tregs, but the expanded Tregs have poor suppressive function and exhibit features of exhaustion. We also show that OX40 enables the activation of the Akt and Stat5 pathways in Tregs, resulting in transient proliferation of Tregs and reduced levels of Foxp3 expression. This creates a state of relative IL-2 deficiency in naive mice that further impacts Tregs. This exhausted Treg phenotype can be prevented by exogenous IL-2, as both OX40 and IL-2 agonists drive further expansion of Tregs in vivo. Importantly, Tregs expanded by both OX40 and IL-2 agonists are potent suppressor cells, and in a heart transplant model, they promote long-term allograft survival. Our data reveal a novel role for OX40 in promoting immune tolerance and may have important clinical implications.
authors.affiliation: Transplant Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Xiang
authors.initials: X
authors.lastname: Xiao
authors.forename: Weihua
authors.initials: W
authors.lastname: Gong
authors.forename: Gulcin
authors.initials: G
authors.lastname: Demirci
authors.forename: Wentao
authors.initials: W
authors.lastname: Liu
authors.forename: Silvia
authors.initials: S
authors.lastname: Spoerl
authors.forename: Xiufeng
authors.initials: X
authors.lastname: Chu
authors.forename: D Keith
authors.initials: DK
authors.lastname: Bishop
authors.forename: Laurence A
authors.initials: LA
authors.lastname: Turka
authors.forename: Xian C
authors.initials: XC
authors.lastname: Li
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D051858:Forkhead Transcription Factors / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D006085:Graft Survival / Q000235:genetics / Q000276:immunology; D016027:Heart Transplantation / Q000276:immunology / Q000473:pathology; D007111:Immunity, Cellular / Q000235:genetics; D007376:Interleukin-2 / Q000172:deficiency / Q000502:physiology; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D053278:OX40 Ligand; D053262:Receptors, OX40 / Q000172:deficiency / Q000378:metabolism / Q000502:physiology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism* / Q000637:transplantation; D023001:Transplantation Tolerance / Q000235:genetics / Q000276:immunology*; D048069:Tumor Necrosis Factors / Q000378:metabolism
chemical_list: D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D007376:Interleukin-2; D008562:Membrane Glycoproteins; D053278:OX40 Ligand; D053262:Receptors, OX40; C505717:Tnfrsf4 protein, mouse; C504586:Tnfsf4 protein, mouse; D048069:Tumor Necrosis Factors