Nitric oxide induces CD4+CD25+ Foxp3 regulatory T cells from CD4+CD25− T cells via p53, IL-2, and OX40

Niedbala, W., Cai, B., Liu, H., Pitman, N., Chang, L. and Liew, F. Y. (2007) Nitric oxide induces CD4+CD25+ Foxp3 regulatory T cells from CD4+CD25− T cells via p53, IL-2, and OX40. Proceedings of the National Academy of Sciences of the United States of America, 104(39), pp. 15478-15483. (doi: 10.1073/pnas.0703725104)

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Publisher's URL: http://dx.doi.org/10.1073/pnas.0703725104

Abstract

The principal aim of the immune system is to establish a balance between defense against pathogens and avoidance of autoimmune disease. This balance is achieved partly through regulatory T cells (Tregs). CD4<sup>+</sup>CD25<sup>+</sup> Tregs are either naturally occurring or induced by antigens and are characterized by the expression of the X-linked forkhead/winged helix transcription factor, Foxp3. Here we report a previously unrecognized subset of CD4<sup>+</sup> CD25<sup>+</sup> Tregs derived from CD4<sup>+</sup> CD25<sup>−</sup> T cells induced by nitric oxide (NO). The induction of Tregs (NO-Tregs) is independent of cGMP but depends on p53, IL-2, and OX40. NO-Tregs produced IL-4 and IL-10, but not IL-2, IFNγ, or TGFβ. The cells were GITR<sup>+</sup>, CD27<sup>+</sup>, T-bet<sup>low</sup>, GATA3<sup>high</sup>, and Foxp3<sup>−</sup>. NO-Tregs suppressed the proliferation of CD4+CD25− T cells in vitro and attenuated colitis- and collagen-induced arthritis in vivo in an IL-10-dependent manner. NO-Tregs also were induced in vivo in SCID mice adoptively transferred with CD4<sup>+</sup>CD25<sup>−</sup> T cells in the presence of LPS and IFNγ, and the induction was completely inhibited by N <sup>G</sup>-monomethyl-L-arginine, a pan NO synthase inhibitor. Therefore, our findings uncovered a previously unrecognized function of NO via the NO–p53–IL-2–OX40–survivin signaling pathway for T cell differentiation and development.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Liew, Prof Foo and Niedbala, Dr Wanda and Pitman, Dr Nick and Cai, Ms Beilei
Authors: Niedbala, W., Cai, B., Liu, H., Pitman, N., Chang, L., and Liew, F. Y.
College/School:College of Medical Veterinary and Life Sciences
College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:Proceedings of the National Academy of Sciences of the United States of America
Publisher:National Academy of Sciences
ISSN:0027-8424
ISSN (Online):1091-6490
Published Online:17 September 2007
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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
378571The role of a novel cytokine (EB13-IL12p35) in asthmaNick PitmanMedical Research Council (MRC)G84/6704Institute of Infection Immunity and Inflammation