Biliary epithelium and liver B cells exposed to bacteria activate intrahepatic MAIT cells through MR1

JOURNAL OF HEPATOLOGY

卷:64

Article

Jeffery, Hannah C.^1,2  van Wilgenburg, Bonnie³  Kurioka, Ayako³  Parekh, Krishan^1,2  Stirling, Kathryn^1,2  Roberts, Sheree^1,2  Dutton, Emma E.⁴  Hunter, Stuart^1,2  Geh, Daniel^1,2  Braitch, Manjit K.^1,2  Rajanayagam, Jeremy^1,2  Iqbal, Tariq⁵  Pinkney, Thomas⁵  Brown, Rachel⁵  Withers, David R.⁴  Adams, David H.^1,2,5  Klenerman, Paul³  Oo, Ye H.^1,2,5 

[1] Univ Birmingham, Inst Immunol & Immunotherapy, Liver Res Ctr, Birmingham B15 2TT, W Midlands, England

[2] Univ Birmingham, Inst Immunol & Immunotherapy, NIHR Biomed Res Unit Liver Dis, Birmingham B15 2TT, W Midlands, England

[3] Univ Oxford, Peter Medawar Bldg Pathogen Res, Oxford OX1 2JD, England

[4] Univ Birmingham, Inst Immunol & Immunotherapy, Birmingham B15 2TT, W Midlands, England

[5] Univ Hosp Birmingham NHS Fdn Trust, Birmingham, W Midlands, England

关键词: Human liver;    Mucosal-associated invariant T cells;    Biliary epithelium;    E. coli;    Immune response;    Biliary firewall;   

DOI  :  10.1016/j.jhep.2015.12.017

来源: Elsevier

【 摘 要 】

Background & Aims: Mucosal-Associated Invariant T (MAIT) cells are innate-like T cells characterised by the invariant TCR-chain, V alpha 7.2-J alpha 33, and are restricted by MR1, which presents bacterial vitamin B metabolites. They are important for antibacterial immunity at mucosal sites; however, detailed characteristics of liver-infiltrating MAIT (LI-MAIT) and their role in biliary immune surveillance remain unexplored. Methods: The phenotype and intrahepatic localisation of human LI-MAIT cells was examined in diseased and normal livers. MAIT cell activation in response to E. coli-exposed macrophages, biliary epithelial cells (BEC) and liver B cells was assessed with/without anti-MR1. Results: Intrahepatic MAIT cells predominantly localised to bile ducts in the portal tracts. Consistent with this distribution, they expressed biliary tropic chemokine receptors CCR6, CXCR6, and integrin alpha E beta 7. LI-MAIT cells were also present in the hepatic sinusoids and possessed tissue-homing chemokine receptor CXCR3 and integrins LFA-1 and VLA-4, suggesting their recruitment via hepatic sinusoids. LI-MAIT cells were enriched in the parenchyma of acute liver failure livers compared to chronic diseased livers. LI-MAIT cells had an activated, effector memory phenotype, expressed alpha 4 beta 7 and receptors for IL-12, IL-18, and IL-23. Importantly, in response to E. coli-exposed macrophages, liver B cells and BEC, MAIT cells upregulated IFN-gamma and CD40 Ligand and degranulated in an MR1-dependent, cytolcine-independent manner. In addition, diseased liver MAIT cells expressed T-bet and ROR gamma t and the cytokines IFN-gamma, TNF-alpha, and IL-17. Conclusions: Our findings provide the first evidence of an immune surveillance effector response for MAIT cells towards BEC in human liver; thus they could be manipulated for treatment of biliary disease in the future. (C) 2016 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

【 授权许可】

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