TY - JOUR
T1 - Disruption of T helper 2-immune responses in Epstein-Barr virus-induced gene 3-deficient mice
AU - Nieuwenhuis, Edward E.S.
AU - Neurath, Markus F.
AU - Corazza, Nadia
AU - Iijima, Hideki
AU - Trgovcich, Joanne
AU - Wirtz, Stefan
AU - Glickman, Jonathan
AU - Bailey, Dan
AU - Yoshida, Masaru
AU - Galle, Peter R.
AU - Kronenberg, Mitchell
AU - Birkenbach, Mark
AU - Blumberg, Richard S.
PY - 2002/12/24
Y1 - 2002/12/24
N2 - 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 α-galactosylceramide (αGalCer)-loaded CD1d-tetramer. iNKT cells from EBI3-/- mice exhibited decreased IL-4 and, to a lesser extent, IFN-γ production after αGalCer stimulation in vitro. A sustained decrease in IL-4 production was also observed in EBI3-/- mice after αGalCer stimulation in vivo in contrast to IFN-γ 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.
AB - 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 α-galactosylceramide (αGalCer)-loaded CD1d-tetramer. iNKT cells from EBI3-/- mice exhibited decreased IL-4 and, to a lesser extent, IFN-γ production after αGalCer stimulation in vitro. A sustained decrease in IL-4 production was also observed in EBI3-/- mice after αGalCer stimulation in vivo in contrast to IFN-γ 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.
KW - Colitis
KW - Cytokines
KW - Dendritic cells
KW - Natural killer T cells
KW - T helper cells
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U2 - 10.1073/pnas.252648899
DO - 10.1073/pnas.252648899
M3 - Article
C2 - 12482940
AN - SCOPUS:0037168543
SN - 0027-8424
VL - 99
SP - 16951
EP - 16956
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 26
ER -