Adoptive transfer of CD8+ T cells from transforming growth factor beta receptor type II (dominant negative form) induces autoimmune cholangitis in mice

Guo Xiang Yang, Zhe Xiong Lian, Ya Hui Chuang, Yuki Moritoki, Ruth Y. Lan, Kanji Wakabayashi, Aftab A. Ansari, Richard A. Flavell, William M. Ridgway, Ross L. Coppel, Koichi Tsuneyama, Ian R. Mackay, M. Eric Gershwin

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Abstract

We recently reported that mice with a T cell-restricted expression of a dominant negative form of transforming growth factor β receptor type II (dnTGFβRII) 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 dnTGFβRII disruption of the liver and/or alternatively the appearance of autoreactive T cells. First, using dnTGFβRIIRagl-/- 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 dnTGFβRII mice into B6/Rag-/- (Ly 5.2) recipients. In unmanipulated dnTGFβRII mice, there was a marked increase in CD4+ and CD8+ T cell biliary infiltrates with AMA. Indeed, B6/Rag-/- recipients of dnTGFβRII 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 dnTGFβRII mice predominantly developed inflammatory bowel disease associated with higher levels of serum interferon γ and tumor necrosis factor α. Conclusion: These data suggest that in this model of PBC, autoreactive CD8 + cells destroy bile ducts.

Original languageEnglish (US)
Pages (from-to)1974-1982
Number of pages9
JournalHepatology
Volume47
Issue number6
DOIs
StatePublished - Jun 2008

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Transforming Growth Factor beta Receptors
Cholangitis
Adoptive Transfer
Growth Factor Receptors
Transforming Growth Factors
Interleukin-2
Biliary Liver Cirrhosis
T-Lymphocytes
Liver
Self Tolerance
Antibodies
Bile Ducts
Inflammatory Bowel Diseases
Interferons
Liver Diseases
Spleen
Tumor Necrosis Factor-alpha
Pathology
Serum

ASJC Scopus subject areas

  • Hepatology
  • Medicine(all)

Cite this

Adoptive transfer of CD8+ T cells from transforming growth factor beta receptor type II (dominant negative form) induces autoimmune cholangitis in mice. / Yang, Guo Xiang; Lian, Zhe Xiong; Chuang, Ya Hui; Moritoki, Yuki; Lan, Ruth Y.; Wakabayashi, Kanji; Ansari, Aftab A.; Flavell, Richard A.; Ridgway, William M.; Coppel, Ross L.; Tsuneyama, Koichi; Mackay, Ian R.; Gershwin, M. Eric.

In: Hepatology, Vol. 47, No. 6, 06.2008, p. 1974-1982.

Research output: Contribution to journalArticle

Yang, GX, Lian, ZX, Chuang, YH, Moritoki, Y, Lan, RY, Wakabayashi, K, Ansari, AA, Flavell, RA, Ridgway, WM, Coppel, RL, Tsuneyama, K, Mackay, IR & Gershwin, ME 2008, 'Adoptive transfer of CD8+ T cells from transforming growth factor beta receptor type II (dominant negative form) induces autoimmune cholangitis in mice', Hepatology, vol. 47, no. 6, pp. 1974-1982. https://doi.org/10.1002/hep.22226
Yang, Guo Xiang ; Lian, Zhe Xiong ; Chuang, Ya Hui ; Moritoki, Yuki ; Lan, Ruth Y. ; Wakabayashi, Kanji ; Ansari, Aftab A. ; Flavell, Richard A. ; Ridgway, William M. ; Coppel, Ross L. ; Tsuneyama, Koichi ; Mackay, Ian R. ; Gershwin, M. Eric. / Adoptive transfer of CD8+ T cells from transforming growth factor beta receptor type II (dominant negative form) induces autoimmune cholangitis in mice. In: Hepatology. 2008 ; Vol. 47, No. 6. pp. 1974-1982.
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AU - Moritoki, Yuki

AU - Lan, Ruth Y.

AU - Wakabayashi, Kanji

AU - Ansari, Aftab A.

AU - Flavell, Richard A.

AU - Ridgway, William M.

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