Nitric oxide induces CD4+CD25+ Foxp3− regulatory T cells from CD4+CD25− T cells via p53, IL-2, and OX40
- *Division of Immunology, Infection, and Inflammation, Glasgow Biomedical Research Centre, 120 University Place, University of Glasgow, Glasgow G12 8TA, United Kingdom; and
- †Institute of Human Genetics, Polish Academy of Science, 60-479, Poznan, Poland
-
Edited by Harvey Cantor, Harvard Medical School, Boston, MA, and approved August 3, 2007 (received for review April 25, 2007)
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+CD25+ 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+CD25+ Tregs derived from CD4+CD25− 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+, CD27+, T-betlow, GATA3high, and Foxp3−. 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+CD25− T cells in the presence of LPS and IFNγ, and the induction was completely inhibited by N G-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.
Footnotes
- ‡To whom correspondence should be addressed. E-mail: f.y.liew{at}clinmed.gla.ac.uk
-
Author contributions: W.N. and F.Y.L. designed research; W.N., B.C., H.L., N.P., and L.C. performed research; W.N., N.P., L.C., and F.Y.L. analyzed data; and F.Y.L. wrote the paper.
-
The authors declare no conflict of interest.
-
This article is a PNAS Direct Submission.
-
This article contains supporting information online at www.pnas.org/cgi/content/full/0703725104/DC1.
- Abbreviations:
- APC,
- antigen-presenting cells;
- CIA,
- collagen-induced arthritis;
- CFSE,
- carboxyfluorescein diacetate succinimidyl ester;
- CII,
- type II collagen;
- NMMA,
- NG-monomethyl- arginine;
- NOS,
- nitric oxide synthase;
- TcR,
- T cell antigen receptor;
- Treg,
- regulatory T cell.
-
Freely available online through the PNAS open access option.
- © 2007 by The National Academy of Sciences of the USA
