title: Clonality, activated antigen-specific CD8(+) T cells, and development of autoimmune cholangitis in dnTGFβRII mice.
abstract: There are several murine models described with features similar to human primary biliary cirrhosis (PBC). Among these models, the one which has the closest serologic features to PBC is a mouse with a T-cell-restricted expression of the dominant negative transforming growth factor β receptor type II (dnTGFβRII). Our work has demonstrated that CD8(+) T cells from dnTGFβRII mice transfer autoimmune cholangitis to Rag1(-/-) recipients. However, it remained unclear whether the autoimmune cholangitis was secondary to an intrinsic function within CD8(+) T cells or due to the abnormal TGFβR environment within which CD8(+) T cells were generated. To address this mechanistic issue, we used our dnTGFβRII, OT-I/Rag1(-/-) , OT-II/Rag1(-/-) mice and in addition generated OT-I/dnTGFβRII/Rag1(-/-) , and OT-II/dnTGFβRII/Rag1(-/-) mice in which the entire T-cell repertoire was replaced with ovalbumin (OVA)-specific CD8(+) or CD4(+) T cells, respectively. Importantly, neither the parental OT-I/dnTGFβRII/Rag1(-/-) mice and/or OT-II/dnTGFβRII/Rag1(-/-) mice developed cholangitis. However, adoptive transfer demonstrated that only transfer of CD8(+) T cells from dnTGFβRII mice but not CD8(+) T cells from OT-I/Rag1(-/-) mice or from OT-I/dnTGFβRII/Rag1(-/-) mice transferred disease. These data were not secondary to an absence of CD4(+) T cell help since a combination of CD8(+) T cells from OT-I/dnTGFβRII/Rag1(-/-) and CD4(+) T cells from OT II/dnTGFβRII/Rag1(-/-) or CD8(+) T cells from OT-I/dnTGFβRII/Rag1(-/-) with CD4(+) T cells from OT-II/Rag1(-/-) mice failed to transfer disease.
  
  
  CONCLUSIONS
  Defective TGFβRII signaling, in addition to clonal CD8(+) T cells that target biliary cells, are required for induction of autoimmune cholangitis.
authors.affiliation: Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis School of Medicine, Davis, CA, USA.
authors.forename: Kazuhito
authors.initials: K
authors.lastname: Kawata
authors.forename: Guo-Xiang
authors.initials: GX
authors.lastname: Yang
authors.forename: Yugo
authors.initials: Y
authors.lastname: Ando
authors.forename: Hajime
authors.initials: H
authors.lastname: Tanaka
authors.forename: Weici
authors.initials: W
authors.lastname: Zhang
authors.forename: Yoshimasa
authors.initials: Y
authors.lastname: Kobayashi
authors.forename: Koichi
authors.initials: K
authors.lastname: Tsuneyama
authors.forename: Patrick S C
authors.initials: PS
authors.lastname: Leung
authors.forename: Zhe-Xiong
authors.initials: ZX
authors.lastname: Lian
authors.forename: William M
authors.initials: WM
authors.lastname: Ridgway
authors.forename: Aftab A
authors.initials: AA
authors.lastname: Ansari
authors.forename: Xiao-Song
authors.initials: XS
authors.lastname: He
authors.forename: M Eric
authors.initials: ME
authors.lastname: Gershwin
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D001327:Autoimmune Diseases / Q000276:immunology / Q000378:metabolism / Q000503:physiopathology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D002761:Cholangitis / Q000276:immunology / Q000378:metabolism / Q000503:physiopathology*; D004195:Disease Models, Animal; D005260:Female; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010047:Ovalbumin / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D037182:T-Cell Antigen Receptor Specificity / Q000502:physiology
chemical_list: D018398:Homeodomain Proteins; D018125:Receptors, Transforming Growth Factor beta; C064658:RAG-1 protein; D010047:Ovalbumin; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II