期刊
JOURNAL OF HEPATOLOGY
卷 64, 期 5, 页码 1118-1127出版社
ELSEVIER
DOI: 10.1016/j.jhep.2015.12.017
关键词
Human liver; Mucosal-associated invariant T cells; Biliary epithelium; E. coli; Immune response; Biliary firewall
资金
- Medical Research Council, United Kingdom [G1002552]
- Queen Elizabeth Hospital Charity, United Kingdom
- NIHR Biomedical Research Unit in liver disease Birmingham, United Kingdom
- Bowel Disease Research Foundation Grant, United Kingdom
- MRC [MC_PC_12020, G1002552, G9818340] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [1511338] Funding Source: researchfish
- Medical Research Council [MC_PC_12020, G1002552, G9818340] Funding Source: researchfish
- National Institute for Health Research [NF-SI-0515-10005, NF-SI-0512-10080, NF-SI-0510-10204] Funding Source: researchfish
- Wellcome Trust [109965/Z/15/Z] Funding Source: researchfish
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.
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