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 r...

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Bibliographic Details
Published in:Blood 2007-10, Vol.110 (7), p.2501-2510
Main Authors: Vu, Minh Diem, Xiao, Xiang, Gao, Wenda, Degauque, Nicolas, Chen, Ming, Kroemer, Alexander, Killeen, Nigel, Ishii, Naoto, Chang Li, Xian
Format: Article
Language:English
Subjects:
Animals
Forkhead Transcription Factors - genetics
Forkhead Transcription Factors - metabolism
Immunobiology
Interferon-gamma - biosynthesis
Lymphocyte Activation - immunology
Mice
Mice, Knockout
Receptors, OX40 - immunology
Receptors, OX40 - metabolism
T-Lymphocytes, Regulatory - immunology
T-Lymphocytes, Regulatory - metabolism
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Summary: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.
ISSN:0006-4971
1528-0020
DOI:10.1182/blood-2007-01-070748