Epstein-Barr virus-induced gene 3 negatively regulates IL-17, IL-22 and RORgamma t.
Epstein-Barr virus-induced gene 3 (EBI3) associates with p28 to form IL-27 and with IL-12p35 to form IL-35. IL-27Ralpha(-/-) mice studies indicate that IL-27 negatively regulates Th17 cell differentiation. However, no EBI3, p28 or p35-deficiency studies that directly address the role of EBI3, p28 or p35 on Th17 cells have been done. Here, we demonstrate that spleen cells derived from EBI3(-/-) mice produce significantly higher levels of IL-17 as well as IL-22 upon stimulation with OVA. In vitro derived EBI3(-/-) Th17 cells also produced significantly higher levels of IL-17 and IL-22 than WT cells. The frequency of IL-17-producing cells was also elevated when EBI3(-/-) cells were cultured under Th17 conditions. In addition, spleen cells from EBI3(-/-) mice immunized with Listeria monocytogenes produced significantly elevated levels of IL-17 and IL-22. Furthermore, the Th17 transcription factor RORgamma t was significantly enhanced in EBI3(-/-) cells. Finally, EBI3(-/-) mice exhibited a reduced bacterial load following an acute challenge with L. monocytogenes or a re-challenge of previously immunized mice, suggesting that EBI3 negatively regulates both innate and adaptive immunity. Taken together, these data provide direct evidence that EBI3 negatively regulates the expression of IL-17, IL-22 and RORgamma t as well as protective immunity against L. monocytogenes.
Yang
Jianfei
J
Department of Immunology and Inflammation, Boehringer Ingelheim Pharmaceuticals, Ridgefield, CT 06877, USA. jianfei.yang@boehringer-ingelheim.com
Yang
Min
M
Htut
Tin Min
TM
Ouyang
Xinshou
X
Hanidu
Adedayo
A
Li
Xiang
X
Sellati
Rosemarie
R
Jiang
Huiping
H
Zhang
Shu
S
Li
Hongxing
H
Zhao
Jie
J
Ting
Adrian T
AT
Mayer
Lloyd
L
Unkeless
Jay C
JC
Labadia
Mark E
ME
Hodge
Martin
M
Li
Jun
J
Xiong
Huabao
H
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D002454:Cell Differentiation / Q000276:immunology; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression / Q000235:genetics; D005786:Gene Expression Regulation; D007371:Interferon-gamma / Q000097:blood / Q000235:genetics / Q000378:metabolism; D020381:Interleukin-17 / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D007378:Interleukins / Q000235:genetics* / Q000378:metabolism*; D008089:Listeria monocytogenes / Q000276:immunology; D008088:Listeriosis / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D015778:Minor Histocompatibility Antigens; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; D010047:Ovalbumin / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology; D018168:Receptors, Retinoic Acid / Q000235:genetics*; D011988:Receptors, Thyroid Hormone / Q000235:genetics*; D013154:Spleen / Q000166:cytology / Q000382:microbiology; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism; D000097043:Interleukin-22
D051858:Forkhead Transcription Factors; D007371:Interferon-gamma; D020381:Interleukin-17; D007378:Interleukins; D015778:Minor Histocompatibility Antigens; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; D010047:Ovalbumin; D011948:Receptors, Antigen, T-Cell; D018168:Receptors, Retinoic Acid; D011988:Receptors, Thyroid Hormone; D014409:Tumor Necrosis Factor-alpha; D000097043:Interleukin-22; C097732:EBI3 protein, human; C498833:Foxp3 protein, mouse; C539900:RORC protein, human; C539901:Rorc protein, mouse