EBI3 deficiency leads to diminished T helper type 1 and increased T helper type 2 mediated airway inflammation.
Despite extensive investigation of the signals required for development of T helper type 1 (Th1) and type 2 (Th2) immune responses, the mechanisms involved are still not well-defined. A critical role for Epstein-Barr virus-induced gene 3 (EBI3) in these responses has been proposed. EBI3, initially discovered as a transcriptionally activated gene in Epstein-Barr virus-infected B lymphocytes, codes for a subunit of the cytokine interleukin-27 (IL-27). While initial studies suggested that it had an important role in promoting Th1 responses, subsequent studies have revealed that EBI3 receptor signalling influences a variety of immune cell types and can inhibit both Th1 and Th2 responses. In the present study, we evaluated EBI3(-/-) mice for their ability to mount both Th1-mediated and Th2-mediated airway inflammatory responses. The EBI3(-/-) mice sensitized by exposure to inhaled ovalbumin plus a high dose of lipopolysaccharide, which normally results in Th1 responses in wild-type (WT) mice, instead developed Th2 type airway inflammation, with increased numbers of eosinophils. The EBI3(-/-) mice that were exposed to inhaled ovalbumin with a low dose of lipopolysaccharide, which induces Th2 responses in WT mice, showed a marked enhancement of these responses, with increased airway eosinophils, increased serum IgE levels and increased levels of Th2 cytokines (IL-4, IL-5 and IL-13) in culture supernatants of mediastinal lymph node cells. Increased production of Th2 cytokines was also seen when naive CD4(+) T cells from EBI3(-/-) mice were stimulated in vitro compared with cells from WT mice. These results provide the first evidence that EBI3 may play an inhibitory role in allergic asthma development.
Department of Pediatrics, Section of Pediatric Pulmonology, Yale University School of Medicine, New Haven, CT, USA. edokme@lsuhsc.edu
Elif
E
Dokmeci
Lan
L
Xu
Eve
E
Robinson
Kseniya
K
Golubets
Kim
K
Bottomly
Christina A
CA
Herrick
D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D004804:Eosinophils / Q000166:cytology / Q000276:immunology; D005260:Female; D007118:Immunoassay / Q000379:methods; D007073:Immunoglobulin E / Q000097:blood / Q000276:immunology; D007074:Immunoglobulin G / Q000097:blood / Q000276:immunology; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D018664:Interleukin-12 / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000276:immunology; D008198:Lymph Nodes / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D015778:Minor Histocompatibility Antigens; D009504:Neutrophils / Q000166:cytology / Q000276:immunology; D010047:Ovalbumin / Q000276:immunology; D011014:Pneumonia / Q000235:genetics / Q000276:immunology*; D018121:Receptors, Cytokine / Q000235:genetics / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology* / Q000378:metabolism; D018418:Th2 Cells / Q000276:immunology* / Q000378:metabolism
D016207:Cytokines; C499601:Ebi3 protein, mouse; D007074:Immunoglobulin G; D008070:Lipopolysaccharides; D015778:Minor Histocompatibility Antigens; D018121:Receptors, Cytokine; D018664:Interleukin-12; D007073:Immunoglobulin E; D007371:Interferon-gamma; D010047:Ovalbumin
Immunity. 2002 Jun;16(6):779-90
12121660
Lancet. 2000 Dec 23-30;356(9248):2149-53
11191543
J Clin Invest. 2000 Mar;105(6):765-75
10727445
J Immunol. 2004 Nov 1;173(9):5626-34
15494513
Blood. 2000 Sep 15;96(6):2206-14
10979967
J Pathol. 2004 Feb;202(2):164-71
14743498
Nature. 1996 Oct 31;383(6603):787-93
8893001
Trends Immunol. 2003 Apr;24(4):207-12
12697453
Proc Natl Acad Sci U S A. 2002 Dec 24;99(26):16951-6
12482940
Annu Rev Immunol. 1999;17:255-81
10358759
Am J Pathol. 2001 Nov;159(5):1763-76
11696437
J Immunol. 2003 May 15;170(10):4886-90
12734330
Nature. 2000 Oct 19;407(6806):916-20
11057672
Blood. 1994 Jun 15;83(12):3697-704
7515718
J Pathol. 2002 Nov;198(3):310-6
12375263
Immunology. 1990 Oct;71(2):258-65
2228026
J Exp Med. 1999 Nov 1;190(9):1309-18
10544202
J Clin Invest. 1999 Jan;103(2):175-83
9916129
Clin Exp Allergy. 2003 May;33(5):566-72
12752583
Inflamm Bowel Dis. 2001 Aug;7(3):215-20
11515847
N Engl J Med. 1989 Feb 2;320(5):271-7
2911321
Nature. 1993 Mar 18;362(6417):245-8
8384701
Nat Med. 2002 Aug;8(8):885-9
12091879
J Clin Invest. 1992 Oct;90(4):1479-85
1401080
J Exp Med. 2002 Dec 16;196(12):1645-51
12486107
J Exp Med. 1988 Jan 1;167(1):43-56
3257253
Gastroenterology. 1998 Aug;115(2):307-13
9679036
J Immunol. 2006 Jan 1;176(1):237-47
16365415
Immunity. 2003 Nov;19(5):645-55
14614852
J Exp Med. 1993 Feb 1;177(2):573-6
8093895
Med Microbiol Immunol. 2004 Feb;193(1):1-17
12836019
J Virol. 1996 Feb;70(2):1143-53
8551575
Proc Natl Acad Sci U S A. 1997 Oct 28;94(22):12041-6
9342359
Science. 1991 Nov 1;254(5032):707-10
1948049
J Immunol. 2004 Feb 15;172(4):2225-31
14764690
Annu Rev Immunol. 1994;12:295-335
8011284
Immunity. 2001 Oct;15(4):569-78
11672539
Nat Rev Immunol. 2005 Jul;5(7):521-31
15999093