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

作者：Huang Wenting; Kachapati Kritika; Adams David; Wu Yuehong; Leung Patrick S C; Yang Guo Xiang; Zhang Weici; Ansari Aftab A; Flavell Richard A; Gershwin M Eric; Ridgway William M^*

来源：Journal of Autoimmunity, 2014, 50: 123-134.

DOI：10.1016/j.jaut.2014.01.034

• KLRG1(+) CD8 cells
• Primary binary cirrhosis
• T regulatory cells

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-beta receptor type II transgenic mice to delineate critical early immunopathological pathways, and previously showed that dnTGF beta RII CD8 T cells transfer biliary disease. Herein we report significantly increased numbers of hepatic dnTGF beta RII 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 dnTGF beta RII CD8 mediated disease was cell intrinsic or extrinsic. Unexpectedly, mixed (dnTGF beta RII and B6) bone marrow chimeric (BMC) mice were protected from biliary disease compared to dnTGF beta RII 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 dnTGF beta RII 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 dnTGF beta RII Tregs offered no protection, and dnTGF beta RII Treg cells were functionally defective in suppressing effector CD8 T cells in vitro compared to wild type B6 Tregs. In vitro cholangiocyte cytotoxicity assays demonstrated significantly increased numbers of cytotoxic hepatic dnTGF beta RII KLRG1+ CD8 cells compared to B6. Protection from disease by B6 Tregs was associated with elimination of hepatic dnTGF beta RII 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.

• 出版日期2014-5