Murine autoimmune cholangitis requires two hits: Cytotoxic KLRG1+ CD8 effector cells and defective T regulatory cells

Wenting Huang, Kritika Kachapati, David Adams, Yuehong Wu, Patrick S Leung, Guo Xiang Yang, Weici Zhang, Aftab A. Ansari, Richard A. Flavell, M. Eric Gershwin, William M. Ridgway

Research output: Contribution to journalArticle

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Abstract

Primary biliary cirrhosis (PBC) is an enigmatic disease mediated by autoimmune destruction of cholangiocytes in hepatic bile ducts. The early immunological events leading to PBC are poorly understood; clinical signs of disease occur very late in the pathological process. We have used our unique murine model of PBC in dominant-negative TGF-β receptor type II transgenic mice to delineate critical early immunopathological pathways, and previously showed that dnTGFβRII CD8 T cells transfer biliary disease. Herein we report significantly increased numbers of hepatic dnTGFβRII terminally differentiated (KLRG1+) CD8 T cells, a CD8 subset previously shown to be enriched in antigen specific cells during hepatic immune response to viral infections. We performed bone marrow chimera studies to assess whether dnTGFβRII CD8 mediated disease was cell intrinsic or extrinsic. Unexpectedly, mixed (dnTGFβRII and B6) bone marrow chimeric (BMC) mice were protected from biliary disease compared to dnTGFβRII single bone marrow chimerics. To define the protective B6 cell subset, we performed adoptive transfer studies, which showed that co-transfer of B6 Tregs prevented dnTGFβRII CD8 T cell mediated cholangitis. Treg mediated disease protection was associated with significantly decreased numbers of hepatic KLRG1+ CD8 T cells. In contrast, co-transfer of dnTGFβRII Tregs offered no protection, and dnTGFβRII Treg cells were functionally defective in suppressing effector CD8 T cells invitro compared to wild type B6 Tregs. Invitro cholangiocyte cytotoxicity assays demonstrated significantly increased numbers of cytotoxic hepatic dnTGFβRII KLRG1+ CD8 cells compared to B6. Protection from disease by B6 Tregs was associated with elimination of hepatic dnTGFβRII CD8 mediated cholangiocyte cytotoxicity. These results emphasize that autoimmune cholangitis requires defects in both the T effector and regulatory compartments, and that an intrinsic T cell effector defect is not sufficient to mediate autoimmune biliary disease in the setting of intact immune regulation. These results have important implications for understanding the early pathogenesis of human PBC.

Original languageEnglish (US)
Pages (from-to)123-134
Number of pages12
JournalJournal of Autoimmunity
Volume50
DOIs
StatePublished - 2014

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Cholangitis
Regulatory T-Lymphocytes
Biliary Liver Cirrhosis
T-Lymphocytes
Bone Marrow
Autoimmune Diseases
Liver
Common Hepatic Duct
Adoptive Transfer
Virus Diseases
Pathologic Processes
Bile Ducts
Transgenic Mice
Hepatocytes
Antigens

Keywords

  • Primary biliary cirrhosis
  • T regulatory cells

ASJC Scopus subject areas

  • Immunology
  • Immunology and Allergy
  • Medicine(all)

Cite this

Murine autoimmune cholangitis requires two hits : Cytotoxic KLRG1+ CD8 effector cells and defective T regulatory cells. / Huang, Wenting; Kachapati, Kritika; Adams, David; Wu, Yuehong; Leung, Patrick S; Yang, Guo Xiang; Zhang, Weici; Ansari, Aftab A.; Flavell, Richard A.; Gershwin, M. Eric; Ridgway, William M.

In: Journal of Autoimmunity, Vol. 50, 2014, p. 123-134.

Research output: Contribution to journalArticle

Huang, Wenting ; Kachapati, Kritika ; Adams, David ; Wu, Yuehong ; Leung, Patrick S ; Yang, Guo Xiang ; Zhang, Weici ; Ansari, Aftab A. ; Flavell, Richard A. ; Gershwin, M. Eric ; Ridgway, William M. / Murine autoimmune cholangitis requires two hits : Cytotoxic KLRG1+ CD8 effector cells and defective T regulatory cells. In: Journal of Autoimmunity. 2014 ; Vol. 50. pp. 123-134.
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abstract = "Primary biliary cirrhosis (PBC) is an enigmatic disease mediated by autoimmune destruction of cholangiocytes in hepatic bile ducts. The early immunological events leading to PBC are poorly understood; clinical signs of disease occur very late in the pathological process. We have used our unique murine model of PBC in dominant-negative TGF-β receptor type II transgenic mice to delineate critical early immunopathological pathways, and previously showed that dnTGFβRII CD8 T cells transfer biliary disease. Herein we report significantly increased numbers of hepatic dnTGFβRII terminally differentiated (KLRG1+) CD8 T cells, a CD8 subset previously shown to be enriched in antigen specific cells during hepatic immune response to viral infections. We performed bone marrow chimera studies to assess whether dnTGFβRII CD8 mediated disease was cell intrinsic or extrinsic. Unexpectedly, mixed (dnTGFβRII and B6) bone marrow chimeric (BMC) mice were protected from biliary disease compared to dnTGFβRII single bone marrow chimerics. To define the protective B6 cell subset, we performed adoptive transfer studies, which showed that co-transfer of B6 Tregs prevented dnTGFβRII CD8 T cell mediated cholangitis. Treg mediated disease protection was associated with significantly decreased numbers of hepatic KLRG1+ CD8 T cells. In contrast, co-transfer of dnTGFβRII Tregs offered no protection, and dnTGFβRII Treg cells were functionally defective in suppressing effector CD8 T cells invitro compared to wild type B6 Tregs. Invitro cholangiocyte cytotoxicity assays demonstrated significantly increased numbers of cytotoxic hepatic dnTGFβRII KLRG1+ CD8 cells compared to B6. Protection from disease by B6 Tregs was associated with elimination of hepatic dnTGFβRII CD8 mediated cholangiocyte cytotoxicity. These results emphasize that autoimmune cholangitis requires defects in both the T effector and regulatory compartments, and that an intrinsic T cell effector defect is not sufficient to mediate autoimmune biliary disease in the setting of intact immune regulation. These results have important implications for understanding the early pathogenesis of human PBC.",
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