title: Classical Th1 cells obtain colitogenicity by co-existence of RORγt-expressing T cells in experimental colitis.
abstract: BACKGROUND
  Both Th1 and Th17 cell types are involved in the pathogenesis of chronic intestinal inflammation. We recently demonstrated that retinoid-related orphan receptor gamma t (RORγt)-expressing Th17 cells are progenitor cells for alternative Th1 cells, which have the potential to induce colitis. However, the involvement of classical Th1 (cTh1) cells generated directly from naive T cells without RORγt expression in the pathogenesis of colitis remains poorly understood.
  
  
  METHODS
  We performed a series of in vivo experiments using a murine chronic colitis model induced by adoptive transfer of splenic CD4CD45RB(high) T cells obtained from wild-type, RORγt(gfp/gfp), or RORγt(gfp/gfp) mice into RAG-2(-/-) mice.
  
  
  RESULTS
  RAG-2(-/-) mice receiving transfer of in vitro-manipulated RORγt(gfp/gfp) Th1 cells developed colitis. RAG-2(-/-) mice co-transferred with splenic CD4CD45RB(high) T cells obtained from wild-type mice and RORγt(gfp/gfp) mice developed colitis with a significant increase in RORγt cTh1 cell numbers when compared with noncolitic mice transferred with splenic CD4CD45RB(high) T cells obtained from RORγt(gfp/gfp) mice. Furthermore, RAG-2(-/-) mice transferred with in vivo-manipulated RORγt(gfp/gfp) cTh1 cells developed colitis with a significant increase in RORγt(gfp/gfp) cTh1 cell numbers.
  
  
  CONCLUSIONS
  These findings indicate that both alternative Th1 cells and cTh1 cells have the potential to be colitogenic in an adaptive transfer model. The development of cTh1 cells was dependent on the co-existence of RORγt-expressing T cells, suggesting a critical role for the interactions of these cell types in the development of chronic intestinal inflammation.
authors.affiliation: *Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan; †Pharmacology Department, Central Research Laboratories, Kaken Pharmaceutical Co. Ltd., Kyoto, Japan; ‡Department of Microbiology and Immunology, Keio University School of Medicine, Tokyo, Japan; and §Research Laboratory, Miyarisan Pharmaceutical, Saitama, Japan.
authors.forename: Keiichiro
authors.initials: K
authors.lastname: Saigusa
authors.forename: Tadakazu
authors.initials: T
authors.lastname: Hisamatsu
authors.forename: Tango
authors.initials: T
authors.lastname: Handa
authors.forename: Tomohisa
authors.initials: T
authors.lastname: Sujino
authors.forename: Yohei
authors.initials: Y
authors.lastname: Mikami
authors.forename: Atsushi
authors.initials: A
authors.lastname: Hayashi
authors.forename: Shinta
authors.initials: S
authors.lastname: Mizuno
authors.forename: Kozue
authors.initials: K
authors.lastname: Takeshita
authors.forename: Toshiro
authors.initials: T
authors.lastname: Sato
authors.forename: Katsuyoshi
authors.initials: K
authors.lastname: Matsuoka
authors.forename: Takanori
authors.initials: T
authors.lastname: Kanai
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002454:Cell Differentiation; D002478:Cells, Cultured; D003092:Colitis / Q000209:etiology / Q000378:metabolism / Q000473:pathology*; D004268:DNA-Binding Proteins / Q000502:physiology*; D004195:Disease Models, Animal; D005434:Flow Cytometry; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D017493:Leukocyte Common Antigens / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000502:physiology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D058504:Th17 Cells / Q000276:immunology* / Q000378:metabolism / Q000473:pathology
chemical_list: D004268:DNA-Binding Proteins; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; C499308:Rag2 protein, mouse; C539901:Rorc protein, mouse; D049452:Green Fluorescent Proteins; D017493:Leukocyte Common Antigens