Nitric oxide induces CD4+CD25+ Foxp3 regulatory T cells from CD4+CD25 T cells via p53, IL-2, and OX40.
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, IFNgamma, or TGFbeta. The cells were GITR(+), CD27(+), T-bet(low), GATA3(high), 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 IFNgamma, 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.
Niedbala
Wanda
W
Division of Immunology, Infection, and Inflammation, Glasgow Biomedical Research Centre, 120 University Place, University of Glasgow, Glasgow G12 8TA, United Kingdom.
Cai
Beilei
B
Liu
Haiying
H
Pitman
Nick
N
Chang
Lynda
L
Liew
Foo Y
FY
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000378:metabolism*; D049109:Cell Proliferation; D003092:Colitis / Q000378:metabolism; D051858:Forkhead Transcription Factors / Q000096:biosynthesis*; D007249:Inflammation; D007376:Interleukin-2 / Q000378:metabolism*; D053645:Interleukin-2 Receptor alpha Subunit / Q000096:biosynthesis*; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D008954:Models, Biological; D009569:Nitric Oxide / Q000378:metabolism*; D053262:Receptors, OX40 / Q000096:biosynthesis*; D013601:T-Lymphocytes / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D007376:Interleukin-2; D053645:Interleukin-2 Receptor alpha Subunit; D053262:Receptors, OX40; C505717:Tnfrsf4 protein, mouse; D016159:Tumor Suppressor Protein p53; D009569:Nitric Oxide