title: Biliary epithelium and liver B cells exposed to bacteria activate intrahepatic MAIT cells through MR1.
abstract: OBJECTIVE
  Mucosal-Associated Invariant T (MAIT) cells are innate-like T cells characterised by the invariant TCR-chain, Vα7.2-Jα33, 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 αEβ7. 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 α4β7 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-γ and CD40 Ligand and degranulated in an MR1-dependent, cytokine-independent manner. In addition, diseased liver MAIT cells expressed T-bet and RORγt and the cytokines IFN-γ, TNF-α, 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.
authors.affiliation: Centre for Liver Research and NIHR Biomedical Research Unit in Liver Disease, Institute of Immunology & Immunotherapy, University of Birmingham, United Kingdom.
authors.forename: Hannah C
authors.initials: HC
authors.lastname: Jeffery
authors.affiliation: Peter Medawar Building for Pathogen Research, University of Oxford, United Kingdom.
authors.forename: Bonnie
authors.initials: B
authors.lastname: van Wilgenburg
authors.affiliation: Peter Medawar Building for Pathogen Research, University of Oxford, United Kingdom.
authors.forename: Ayako
authors.initials: A
authors.lastname: Kurioka
authors.affiliation: Centre for Liver Research and NIHR Biomedical Research Unit in Liver Disease, Institute of Immunology & Immunotherapy, University of Birmingham, United Kingdom.
authors.forename: Krishan
authors.initials: K
authors.lastname: Parekh
authors.affiliation: Centre for Liver Research and NIHR Biomedical Research Unit in Liver Disease, Institute of Immunology & Immunotherapy, University of Birmingham, United Kingdom.
authors.forename: Kathryn
authors.initials: K
authors.lastname: Stirling
authors.affiliation: Centre for Liver Research and NIHR Biomedical Research Unit in Liver Disease, Institute of Immunology & Immunotherapy, University of Birmingham, United Kingdom.
authors.forename: Sheree
authors.initials: S
authors.lastname: Roberts
authors.affiliation: Institute of Immunology and Immunotherapy, University of Birmingham, United Kingdom.
authors.forename: Emma E
authors.initials: EE
authors.lastname: Dutton
authors.affiliation: Centre for Liver Research and NIHR Biomedical Research Unit in Liver Disease, Institute of Immunology & Immunotherapy, University of Birmingham, United Kingdom.
authors.forename: Stuart
authors.initials: S
authors.lastname: Hunter
authors.affiliation: Centre for Liver Research and NIHR Biomedical Research Unit in Liver Disease, Institute of Immunology & Immunotherapy, University of Birmingham, United Kingdom.
authors.forename: Daniel
authors.initials: D
authors.lastname: Geh
authors.affiliation: Centre for Liver Research and NIHR Biomedical Research Unit in Liver Disease, Institute of Immunology & Immunotherapy, University of Birmingham, United Kingdom.
authors.forename: Manjit K
authors.initials: MK
authors.lastname: Braitch
authors.affiliation: Centre for Liver Research and NIHR Biomedical Research Unit in Liver Disease, Institute of Immunology & Immunotherapy, University of Birmingham, United Kingdom.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Rajanayagam
authors.affiliation: University Hospital of Birmingham NHS Foundation Trust, United Kingdom.
authors.forename: Tariq
authors.initials: T
authors.lastname: Iqbal
authors.affiliation: University Hospital of Birmingham NHS Foundation Trust, United Kingdom.
authors.forename: Thomas
authors.initials: T
authors.lastname: Pinkney
authors.affiliation: University Hospital of Birmingham NHS Foundation Trust, United Kingdom.
authors.forename: Rachel
authors.initials: R
authors.lastname: Brown
authors.affiliation: Institute of Immunology and Immunotherapy, University of Birmingham, United Kingdom.
authors.forename: David R
authors.initials: DR
authors.lastname: Withers
authors.affiliation: Centre for Liver Research and NIHR Biomedical Research Unit in Liver Disease, Institute of Immunology & Immunotherapy, University of Birmingham, United Kingdom; University Hospital of Birmingham NHS Foundation Trust, United Kingdom.
authors.forename: David H
authors.initials: DH
authors.lastname: Adams
authors.affiliation: Peter Medawar Building for Pathogen Research, University of Oxford, United Kingdom.
authors.forename: Paul
authors.initials: P
authors.lastname: Klenerman
authors.affiliation: Centre for Liver Research and NIHR Biomedical Research Unit in Liver Disease, Institute of Immunology & Immunotherapy, University of Birmingham, United Kingdom; University Hospital of Birmingham NHS Foundation Trust, United Kingdom. Electronic address: y.h.oo@bham.ac.uk.
authors.forename: Ye H
authors.initials: YH
authors.lastname: Oo
mesh_terms: D001402:B-Lymphocytes / Q000276:immunology* / Q000473:pathology; D001653:Bile Ducts, Intrahepatic / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D004926:Escherichia coli; D006801:Humans; D007113:Immunity, Innate; D008099:Liver / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D008213:Lymphocyte Activation / Q000276:immunology*; D000072336:Mucosal-Associated Invariant T Cells / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000276:immunology*
keywords: Biliary epithelium; Biliary firewall; E. coli; Human liver; Immune response; Mucosal-associated invariant T cells