title: Adoptive transfer of CD8(+) T cells from transforming growth factor beta receptor type II (dominant negative form) induces autoimmune cholangitis in mice.
abstract: We recently reported that mice with a T cell-restricted expression of a dominant negative form of transforming growth factor beta receptor type II (dnTGFbetaRII) spontaneously develop autoimmune cholangitis that resembles human primary biliary cirrhosis (PBC), including antimitochondrial antibodies (AMAs) and extensive portal CD4(+) and CD8(+) lymphocytic infiltrates. On the basis of these data, we performed a series of experiments to determine whether the pathology was secondary to direct dnTGFbetaRII disruption of the liver and/or alternatively the appearance of autoreactive T cells. First, using dnTGFbetaRIIRag1(-/-) mice, we noted a normal hepatic and biliary structure. Hence, we performed a rigorous series of adoptive transfer studies, transferring Ly5.1(+) unfractionated spleen cell CD4(+) or CD8(+) T cells from dnTGFbetaRII mice into B6/Rag(-/-) (Ly 5.2) recipients. In unmanipulated dnTGFbetaRII mice, there was a marked increase in CD4(+) and CD8(+) T cell biliary infiltrates with AMA. Indeed, B6/Rag(-/-) recipients of dnTGFbetaRII unfractionated cells develop features of liver disease similar to PBC, suggesting that splenic loss of self-tolerance alone is sufficient to cause disease in this model and therefore that there is no specific abnormality in the biliary targets required for appearance of disease. More importantly, adoptive transfer of CD8(+) but not CD4(+) T cells into B6/Rag(-/-) mice led to liver histopathology remarkably similar to PBC, emphasizing a prominent role for CD8 T cell-mediated pathogenesis. In contrast, B6/Rag(-/-) recipients of CD4(+) T cells from dnTGFbetaRII mice predominantly developed inflammatory bowel disease associated with higher levels of serum interferon gamma and tumor necrosis factor alpha.
  
  
  CONCLUSIONS
  These data suggest that in this model of PBC, autoreactive CD8(+) cells destroy bile ducts.
authors.affiliation: Division of Rheumatology, University of California at Davis, Davis, CA 95616, USA.
authors.forename: Guo-Xiang
authors.initials: GX
authors.lastname: Yang
authors.forename: Zhe-Xiong
authors.initials: ZX
authors.lastname: Lian
authors.forename: Ya-Hui
authors.initials: YH
authors.lastname: Chuang
authors.forename: Yuki
authors.initials: Y
authors.lastname: Moritoki
authors.forename: Ruth Y
authors.initials: RY
authors.lastname: Lan
authors.forename: Kanji
authors.initials: K
authors.lastname: Wakabayashi
authors.forename: Aftab A
authors.initials: AA
authors.lastname: Ansari
authors.forename: Richard A
authors.initials: RA
authors.lastname: Flavell
authors.forename: William M
authors.initials: WM
authors.lastname: Ridgway
authors.forename: Ross L
authors.initials: RL
authors.lastname: Coppel
authors.forename: Koichi
authors.initials: K
authors.lastname: Tsuneyama
authors.forename: Ian R
authors.initials: IR
authors.lastname: Mackay
authors.forename: M Eric
authors.initials: ME
authors.lastname: Gershwin
mesh_terms: D019264:Adoptive Transfer / Q000009:adverse effects*; D000818:Animals; D001327:Autoimmune Diseases / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D001652:Bile Ducts / Q000378:metabolism / Q000473:pathology; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000473:pathology*; D002761:Cholangitis / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D004195:Disease Models, Animal; D005260:Female; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008105:Liver Cirrhosis, Biliary / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D045522:Recombinases / Q000235:genetics / Q000378:metabolism
chemical_list: D018125:Receptors, Transforming Growth Factor beta; D045522:Recombinases; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II