title: Relevance of sexual dimorphism to regulatory T cells: estradiol promotes IFN-gamma production by invariant natural killer T cells.
abstract: Mechanisms accounting for gender dimorphism during immune responses are still poorly understood. Since invariant natural killer T (iNKT) cells exert important regulatory functions through their capacity to produce both T helper 1 (Th1) and Th2 cytokines, we addressed the question of whether these activities could be modulated by sexual hormones. We found that in vivo challenge with the specific ligand of iNKT cells, alpha-galactosylceramide (alpha-GalCer), induced significantly higher concentrations of interferon gamma (IFN-gamma) in the serum of female than in that of male mice, while interleukin 4 (IL-4) production was not modified. In support of a crucial role of ovarian hormones in this phenomenon, a significant decrease of serum IFN-gamma concentrations occurred in ovariectomized females, in response to treatment with alpha-GalCer, while orchidectomy affected neither IFN-gamma nor IL-4 serum concentrations in males. The implication of estrogens in this selective enhancement of IFN-gamma production by iNKT cells was demonstrated by (1) the increased alpha-GalCer-induced IFN-gamma synthesis by iNKT cells upon both in vitro and in vivo exposure to estradiol and (2) the abolition of the sex-linked difference in alpha-GalCer-induced IFN-gamma release in estrogen receptor alpha-deficient mice. These results provide the first evidence that estrogens influence iNKT cells leading to this gender dimorphism in their cytokine production profile.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM) U589, Institut L. Bugnard, Centre Hospitalier et Universitaire (CHU) Rangueil, Toulouse, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Gourdy
authors.forename: Luiza M
authors.initials: LM
authors.lastname: Araujo
authors.forename: Ren
authors.initials: R
authors.lastname: Zhu
authors.forename: Barbara
authors.initials: B
authors.lastname: Garmy-Susini
authors.forename: Séverine
authors.initials: S
authors.lastname: Diem
authors.forename: Henrik
authors.initials: H
authors.lastname: Laurell
authors.forename: Maria
authors.initials: M
authors.lastname: Leite-de-Moraes
authors.forename: Michel
authors.initials: M
authors.lastname: Dy
authors.forename: Jean François
authors.initials: JF
authors.lastname: Arnal
authors.forename: Francis
authors.initials: F
authors.lastname: Bayard
authors.forename: André
authors.initials: A
authors.lastname: Herbelin
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004958:Estradiol / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology*; D047628:Estrogen Receptor alpha / Q000172:deficiency / Q000276:immunology; D005260:Female; D005699:Galactosylceramides / Q000008:administration & dosage / Q000276:immunology; D007371:Interferon-gamma / Q000097:blood / Q000276:immunology*; D015847:Interleukin-4 / Q000097:blood / Q000276:immunology; D007694:Killer Cells, Natural / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects* / Q000276:immunology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009919:Orchiectomy; D010052:Ovariectomy; D012727:Sex Characteristics; D006377:T-Lymphocytes, Helper-Inducer / Q000166:cytology / Q000276:immunology* / Q000378:metabolism
chemical_list: D047628:Estrogen Receptor alpha; D005699:Galactosylceramides; D015847:Interleukin-4; D004958:Estradiol; D007371:Interferon-gamma