title: Increased Th17 and regulatory T cell responses in EBV-induced gene 3-deficient mice lead to marginally enhanced development of autoimmune encephalomyelitis.
abstract: EBV-induced gene 3 (EBI3)-encoded protein can form heterodimers with IL-27P28 and IL-12P35 to form IL-27 and IL-35. IL-27 and IL-35 may influence autoimmunity by inhibiting Th17 differentiation and facilitating the inhibitory roles of Foxp3(+) regulatory T (Treg) cells, respectively. In this study, we have evaluated the development of experimental autoimmune encephalomyelitis (EAE) in EBI3-deficient mice that lack both IL-27 and IL-35. We found that myelin oligodendrocyte glycoprotein peptide immunization resulted in marginally enhanced EAE development in EBI3-deficient C57BL6 and 2D2 TCR-transgenic mice. EBI3 deficiency resulted in significantly increased Th17 and Th1 responses in the CNS and increased T cell production of IL-2 and IL-17 in the peripheral lymphoid organs. EBI3-deficient and -sufficient 2D2 T cells had equal ability in inducing EAE in Rag1(-/-) mice; however, more severe disease was induced in EBI3(-/-)Rag1(-/-) mice than in Rag1(-/-) mice by 2D2 T cells. EBI3-deficient mice had increased numbers of CD4(+)Foxp3(+) Treg cells in peripheral lymphoid organs. More strikingly, EBI3-deficient Treg cells had more potent suppressive functions in vitro and in vivo. Thus, our data support an inhibitory role for EBI3 in Th17, Th1, IL-2, and Treg responses. Although these observations are consistent with the known functions of IL-27, the IL-35 contribution to the suppressive functions of Treg cells is not evident in this model. Increased Treg responses in EBI3(-/-) mice may explain why the EAE development is only modestly enhanced compared with wild-type mice.
authors.affiliation: Department of Pathology, The Ohio State University Medical Center, Columbus, OH 43210, USA.
authors.forename: Jin-Qing
authors.initials: JQ
authors.lastname: Liu
authors.forename: Zhenzhen
authors.initials: Z
authors.lastname: Liu
authors.forename: Xuejun
authors.initials: X
authors.lastname: Zhang
authors.forename: Yun
authors.initials: Y
authors.lastname: Shi
authors.forename: Fatemeh
authors.initials: F
authors.lastname: Talebian
authors.forename: Joseph W
authors.initials: JW
authors.lastname: Carl
authors.forename: Chuan
authors.initials: C
authors.lastname: Yu
authors.forename: Fu-Dong
authors.initials: FD
authors.lastname: Shi
authors.forename: Caroline C
authors.initials: CC
authors.lastname: Whitacre
authors.forename: Joanne
authors.initials: J
authors.lastname: Trgovcich
authors.forename: Xue-Feng
authors.initials: XF
authors.lastname: Bai
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000209:etiology / Q000276:immunology*; D051858:Forkhead Transcription Factors / Q000032:analysis; D005786:Gene Expression Regulation / Q000276:immunology; D018398:Homeodomain Proteins / Q000276:immunology; D007165:Immunosuppression Therapy; D007376:Interleukin-2 / Q000276:immunology; D007378:Interleukins / Q000172:deficiency / Q000276:immunology; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D015778:Minor Histocompatibility Antigens; D012333:RNA, Messenger / Q000096:biosynthesis; D018121:Receptors, Cytokine / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D037182:T-Cell Antigen Receptor Specificity; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology; D058504:Th17 Cells / Q000276:immunology*
chemical_list: C499601:Ebi3 protein, mouse; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D018398:Homeodomain Proteins; C486767:Il27 protein, mouse; D007376:Interleukin-2; D007378:Interleukins; D015778:Minor Histocompatibility Antigens; D012333:RNA, Messenger; D018121:Receptors, Cytokine; C569375:interleukin-35, mouse; C064658:RAG-1 protein