Liver-resident NK Cells Suppress Autoimmune Cholangitis and Limit the Proliferation of CD4 T Cells

Overview

Journal Cell Mol Immunol

Date 2019 Mar 16

PMID 30874628

Citations 17

Authors

Zhi-Bin Zhao

Fang-Ting Lu

Hong-Di Ma

Yin-Hu Wang

Wei Yang

Jie Long

Qi Miao

Weici Zhang

Zhigang Tian

William M Ridgway

Jie Cao

M Eric Gershwin

Zhe-Xiong Lian

Affiliations

Soon will be listed here.

Abstract

Liver-resident NK cells are distinct from conventional NK cells and play an important role in the maintenance of liver homeostasis. How liver-resident NK cells participate in autoimmune cholangitis remains unclear. Here, we extensively investigated the impact of NK cells in the pathogenesis of autoimmune cholangitis utilizing the well-established dnTGFβRII cholangitis model, NK cell-deficient (Nfil3) mice, adoptive transfer and in vivo antibody-mediated NK cell depletion. Our data demonstrated that disease progression was associated with a significantly reduced frequency of hepatic NK cells. Depletion of NK cells resulted in exacerbated autoimmune cholangitis in dnTGFβRII mice. We further confirmed that the DX5CD11c liver-resident NK cell subset colocalized with CD4 T cells and inhibited CD4 T cell proliferation. Gene expression microarray analysis demonstrated that liver-resident NK cells had a distinct gene expression pattern consisting of the increased expression of genes involved in negative regulatory functions in the context of the inflammatory microenvironment.

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References

Hirschfield G, Gershwin M . The immunobiology and pathophysiology of primary biliary cirrhosis. Annu Rev Pathol. 2013; 8:303-30. DOI: 10.1146/annurev-pathol-020712-164014. View

Gershwin M, Mackay I . The causes of primary biliary cirrhosis: Convenient and inconvenient truths. Hepatology. 2007; 47(2):737-45. DOI: 10.1002/hep.22042. View

Selmi C, Meda F, Kasangian A, Invernizzi P, Tian Z, Lian Z . Experimental evidence on the immunopathogenesis of primary biliary cirrhosis. Cell Mol Immunol. 2009; 7(1):1-10. PMC: 4003255. DOI: 10.1038/cmi.2009.104. View

Tomiyama T, Yang G, Zhao M, Zhang W, Tanaka H, Wang J . The modulation of co-stimulatory molecules by circulating exosomes in primary biliary cirrhosis. Cell Mol Immunol. 2015; 14(3):276-284. PMC: 5360882. DOI: 10.1038/cmi.2015.86. View

Chuang Y, Lian Z, Tsuneyama K, Chiang B, Ansari A, Coppel R . Increased killing activity and decreased cytokine production in NK cells in patients with primary biliary cirrhosis. J Autoimmun. 2006; 26(4):232-40. DOI: 10.1016/j.jaut.2006.04.001. View

Gorelik L, Flavell R . Abrogation of TGFbeta signaling in T cells leads to spontaneous T cell differentiation and autoimmune disease. Immunity. 2000; 12(2):171-81. DOI: 10.1016/s1074-7613(00)80170-3. View

Oertelt S, Lian Z, Cheng C, Chuang Y, Padgett K, He X . Anti-mitochondrial antibodies and primary biliary cirrhosis in TGF-beta receptor II dominant-negative mice. J Immunol. 2006; 177(3):1655-60. DOI: 10.4049/jimmunol.177.3.1655. View

Ma H, Ma W, Liu Q, Zhao Z, Liu M, Tsuneyama K . Chemokine receptor CXCR3 deficiency exacerbates murine autoimmune cholangitis by promoting pathogenic CD8 T cell activation. J Autoimmun. 2017; 78:19-28. PMC: 5357510. DOI: 10.1016/j.jaut.2016.12.012. View

Yang G, Lian Z, Chuang Y, Moritoki Y, Lan R, Wakabayashi K . Adoptive transfer of CD8(+) T cells from transforming growth factor beta receptor type II (dominant negative form) induces autoimmune cholangitis in mice. Hepatology. 2008; 47(6):1974-82. PMC: 2749317. DOI: 10.1002/hep.22226. View

10.

Kawata K, Yang G, Ando Y, Tanaka H, Zhang W, Kobayashi Y . Clonality, activated antigen-specific CD8(+) T cells, and development of autoimmune cholangitis in dnTGFβRII mice. Hepatology. 2013; 58(3):1094-104. PMC: 3716874. DOI: 10.1002/hep.26418. View

11.

Moritoki Y, Lian Z, Lindor K, Tuscano J, Tsuneyama K, Zhang W . B-cell depletion with anti-CD20 ameliorates autoimmune cholangitis but exacerbates colitis in transforming growth factor-beta receptor II dominant negative mice. Hepatology. 2009; 50(6):1893-903. PMC: 4130556. DOI: 10.1002/hep.23238. View

12.

Chuang Y, Lian Z, Yang G, Shu S, Moritoki Y, Ridgway W . Natural killer T cells exacerbate liver injury in a transforming growth factor beta receptor II dominant-negative mouse model of primary biliary cirrhosis. Hepatology. 2007; 47(2):571-80. DOI: 10.1002/hep.22052. View

13.

Wang Y, Yang W, Yang J, Jia Y, Tang W, Gershwin M . Systems biologic analysis of T regulatory cells genetic pathways in murine primary biliary cirrhosis. J Autoimmun. 2015; 59:26-37. PMC: 4829434. DOI: 10.1016/j.jaut.2015.01.011. View

14.

Kashiwada M, Pham N, Pewe L, Harty J, Rothman P . NFIL3/E4BP4 is a key transcription factor for CD8α⁺ dendritic cell development. Blood. 2011; 117(23):6193-7. PMC: 3122942. DOI: 10.1182/blood-2010-07-295873. View

15.

Tian Z, Chen Y, Gao B . Natural killer cells in liver disease. Hepatology. 2012; 57(4):1654-62. PMC: 3573257. DOI: 10.1002/hep.26115. View

16.

Gao B . Basic liver immunology. Cell Mol Immunol. 2016; 13(3):265-6. PMC: 4856812. DOI: 10.1038/cmi.2016.09. View

17.

Pelletier S, Drouin C, Bedard N, Khakoo S, Bruneau J, Shoukry N . Increased degranulation of natural killer cells during acute HCV correlates with the magnitude of virus-specific T cell responses. J Hepatol. 2010; 53(5):805-16. PMC: 4178223. DOI: 10.1016/j.jhep.2010.05.013. View

18.

Golden-Mason L, Cox A, Randall J, Cheng L, Rosen H . Increased natural killer cell cytotoxicity and NKp30 expression protects against hepatitis C virus infection in high-risk individuals and inhibits replication in vitro. Hepatology. 2010; 52(5):1581-9. PMC: 2967665. DOI: 10.1002/hep.23896. View

19.

Wen C, He X, Ma H, Hou N, Wei C, Song T . Hepatitis C virus infection downregulates the ligands of the activating receptor NKG2D. Cell Mol Immunol. 2009; 5(6):475-8. PMC: 4072334. DOI: 10.1038/cmi.2008.60. View

20.

Dunn C, Brunetto M, Reynolds G, Christophides T, Kennedy P, Lampertico P . Cytokines induced during chronic hepatitis B virus infection promote a pathway for NK cell-mediated liver damage. J Exp Med. 2007; 204(3):667-80. PMC: 2137916. DOI: 10.1084/jem.20061287. View