title: Disruption of T helper 2-immune responses in Epstein-Barr virus-induced gene 3-deficient mice.
abstract: Epstein-Barr virus-induced gene 3 (EBI3) is a widely expressed IL-12p40-related protein that associates as a heterodimer with either IL-12p35 or an IL-12p35 homologue, p28, to create a new cytokine (IL-27). To define the function of EBI3 in vivo, we generated knockout mice in which the ebi3 gene was targeted by homologous recombination. EBI3-/- mice exhibited normal numbers of both naive and mature CD4+ and CD8+ T cells and B cells, but markedly decreased numbers of invariant natural killer T cells (iNKT) as defined by staining with an alpha-galactosylceramide (alphaGalCer)-loaded CD1d-tetramer. iNKT cells from EBI3-/- mice exhibited decreased IL-4 and, to a lesser extent, IFN-gamma production after alphaGalCer stimulation in vitro. A sustained decrease in IL-4 production was also observed in EBI3-/- mice after alphaGalCer stimulation in vivo in contrast to IFN-gamma production, which was only transiently decreased under such stimulation. Notably, EBI3-/- mice were resistant to the induction of immunopathology associated with oxazolone-induced colitis, a colitis model mediated primarily by T helper (Th) 2-type cytokine production by iNKT cells. In contrast, trinitrobenzene sulfonic acid-induced colitis, a predominantly Th1-mediated colitis model, was unaffected. Thus, EBI3 plays a critical regulatory role in the induction of Th2-type immune responses and the development of Th2-mediated tissue inflammation in vivo, which may be mediated through the control of iNKT cell function.
authors.affiliation: Gastroenterology Division and Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Edward E S
authors.initials: EE
authors.lastname: Nieuwenhuis
authors.forename: Markus F
authors.initials: MF
authors.lastname: Neurath
authors.forename: Nadia
authors.initials: N
authors.lastname: Corazza
authors.forename: Hideki
authors.initials: H
authors.lastname: Iijima
authors.forename: Joanne
authors.initials: J
authors.lastname: Trgovcich
authors.forename: Stefan
authors.initials: S
authors.lastname: Wirtz
authors.forename: Jonathan
authors.initials: J
authors.lastname: Glickman
authors.forename: Dan
authors.initials: D
authors.lastname: Bailey
authors.forename: Masaru
authors.initials: M
authors.lastname: Yoshida
authors.forename: Peter R
authors.initials: PR
authors.lastname: Galle
authors.forename: Mitchell
authors.initials: M
authors.lastname: Kronenberg
authors.forename: Mark
authors.initials: M
authors.lastname: Birkenbach
authors.forename: Richard S
authors.initials: RS
authors.lastname: Blumberg
mesh_terms: D000818:Animals; D006023:Glycoproteins / Q000502:physiology*; D007371:Interferon-gamma / Q000096:biosynthesis; D015847:Interleukin-4 / Q000096:biosynthesis; D007378:Interleukins; D051379:Mice; D008810:Mice, Inbred C57BL; D015778:Minor Histocompatibility Antigens; D018121:Receptors, Cytokine; D013601:T-Lymphocytes / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology*
chemical_list: C097732:EBI3 protein, human; D006023:Glycoproteins; D007378:Interleukins; D015778:Minor Histocompatibility Antigens; D018121:Receptors, Cytokine; D015847:Interleukin-4; D007371:Interferon-gamma