title: Tyrosine kinase 2 plays critical roles in the pathogenic CD4 T cell responses for the development of experimental autoimmune encephalomyelitis.
abstract: Tyrosine kinase 2 (Tyk2), a member of the JAK family, is involved in IL-12- and IL-23-mediated signaling. In the present study, we examined the roles of Tyk2 in the development of myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE) by using Tyk2 knockout (KO) mice. In vitro differentiation of Th1 but not Th17 cells was severely impaired in Tyk2 KO CD4 T cells, although Tyk2 KO Th17 cells did not respond to IL-23. Tyk2 KO mice showed complete resistance against EAE with no infiltration of CD4 T cells in the spinal cord. Surprisingly, the number of MOG-specific Th17 cells in the periphery was comparable between KO and wild-type (WT) mice, whereas Th1 cells were greatly reduced in Tyk2 KO mice. Adoptive transfer of MOG-primed WT T cells induced EAE in Tyk2 KO recipients, indicating that Tyk2 in the environment was dispensable for the infiltration of effector T cells into the spinal cord. A reduced but significant number of Tyk2 KO T cells were detected in the spinal cord of mice with EAE, which had been reconstituted with bone marrow cells of WT and KO mice. Furthermore, MOG-immunized Tyk2 KO mice developed EAE after adoptive transfer of MOG-primed WT Th1 cells, which might trigger local inflammation that recruits Th17 cells. Taken together, these results indicate that Tyk2 is critically involved in the pathogenic CD4 T cell responses and thus could be a target molecule for the treatment of autoimmune diseases.
authors.affiliation: Division of Host Defense, Department of Orthopedic Surgery, Kyushu University, Fukuoka, Japan.
authors.forename: Akiko
authors.initials: A
authors.lastname: Oyamada
authors.forename: Hiori
authors.initials: H
authors.lastname: Ikebe
authors.forename: Momoe
authors.initials: M
authors.lastname: Itsumi
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Saiwai
authors.forename: Seiji
authors.initials: S
authors.lastname: Okada
authors.forename: Kazuya
authors.initials: K
authors.lastname: Shimoda
authors.forename: Yoichiro
authors.initials: Y
authors.lastname: Iwakura
authors.forename: Keiichi I
authors.initials: KI
authors.lastname: Nakayama
authors.forename: Yukihide
authors.initials: Y
authors.lastname: Iwamoto
authors.forename: Yasunobu
authors.initials: Y
authors.lastname: Yoshikai
authors.forename: Hisakata
authors.initials: H
authors.lastname: Yamada
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D002454:Cell Differentiation / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis / Q000276:immunology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D020381:Interleukin-17 / Q000096:biosynthesis / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009185:Myelin Proteins; D018992:Myelin-Associated Glycoprotein / Q000276:immunology; D063308:Myelin-Oligodendrocyte Glycoprotein; D013116:Spinal Cord / Q000276:immunology / Q000473:pathology; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D053634:TYK2 Kinase / Q000235:genetics / Q000276:immunology*; D018417:Th1 Cells / Q000166:cytology / Q000276:immunology
chemical_list: D016207:Cytokines; D020381:Interleukin-17; C571327:Mog protein, mouse; D009185:Myelin Proteins; D018992:Myelin-Associated Glycoprotein; D063308:Myelin-Oligodendrocyte Glycoprotein; D053634:TYK2 Kinase; C499356:Tyk2 protein, mouse