Disruption of T helper 2-immune responses in Epstein-Barr virus-induced gene 3-deficient mice.
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.
Nieuwenhuis
Edward E S
EE
Gastroenterology Division and Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Neurath
Markus F
MF
Corazza
Nadia
N
Iijima
Hideki
H
Trgovcich
Joanne
J
Wirtz
Stefan
S
Glickman
Jonathan
J
Bailey
Dan
D
Yoshida
Masaru
M
Galle
Peter R
PR
Kronenberg
Mitchell
M
Birkenbach
Mark
M
Blumberg
Richard S
RS
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*
C097732:EBI3 protein, human; D006023:Glycoproteins; D007378:Interleukins; D015778:Minor Histocompatibility Antigens; D018121:Receptors, Cytokine; D015847:Interleukin-4; D007371:Interferon-gamma