title: Nitric oxide-induced regulatory T cells inhibit Th17 but not Th1 cell differentiation and function.
abstract: NO is a free radical with pleiotropic functions. We have shown earlier that NO induces a population of CD4(+)CD25(+)Foxp3(-) regulatory T cells (NO-Tregs) that suppress the functions of CD4(+)CD25(-) effector T cells in vitro and in vivo. We report in this study an unexpected finding that NO-Tregs suppressed Th17 but not Th1 cell differentiation and function. In contrast, natural Tregs (nTregs), which suppressed Th1 cells, failed to suppress Th17 cells. Consistent with this observation, NO-Tregs inhibited the expression of retinoic acid-related orphan receptor γt but not T-bet, whereas nTregs suppressed T-bet but not retinoic acid-related orphan receptor γt expression. The NO-Treg-mediated suppression of Th17 was partially cell contact-dependent and was associated with IL-10. In vivo, adoptively transferred NO-Tregs potently attenuated experimental autoimmune encephalomyelitis. The disease suppression was accompanied by a reduction of Th17, but not Th1 cells in the draining lymph nodes, and a decrease in the production of IL-17, but an increase in IL-10 synthesis. Our results therefore demonstrate the differential suppressive function between NO-Tregs and nTregs and indicate specialization of the regulatory mechanism of the immune system.
authors.affiliation: Centre of Immunology, Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, United Kingdom. wanda.niedbala@glasgow.ac.uk
authors.forename: Wanda
authors.initials: W
authors.lastname: Niedbala
authors.forename: Anne-Gaelle
authors.initials: AG
authors.lastname: Besnard
authors.forename: Hui R
authors.initials: HR
authors.lastname: Jiang
authors.forename: Jose C
authors.initials: JC
authors.lastname: Alves-Filho
authors.forename: Sandra Y
authors.initials: SY
authors.lastname: Fukada
authors.forename: Daniela
authors.initials: D
authors.lastname: Nascimento
authors.forename: Akio
authors.initials: A
authors.lastname: Mitani
authors.forename: Peter
authors.initials: P
authors.lastname: Pushparaj
authors.forename: Mohammed H
authors.initials: MH
authors.lastname: Alqahtani
authors.forename: Foo Y
authors.initials: FY
authors.lastname: Liew
mesh_terms: D000818:Animals; D002450:Cell Communication / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology*; D002478:Cells, Cultured; D005260:Female; D006131:Growth Inhibitors / Q000494:pharmacology / Q000502:physiology*; D007108:Immune Tolerance / Q000276:immunology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000494:pharmacology / Q000502:physiology*; D061251:Primary Cell Culture; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology*; D018417:Th1 Cells / Q000166:cytology / Q000276:immunology*; D058504:Th17 Cells / Q000166:cytology / Q000276:immunology*
chemical_list: D006131:Growth Inhibitors; D009569:Nitric Oxide