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Cited by 212Liver Diseases and ImmunityT-cell and B-cell ImmunologyPediatric Hepatobiliary Diseases and Treatments

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

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Jeffery, Hannah C., van Wilgenburg, Bonnie, Kurioka, Ayako, Parekh, Krishan, Stirling, Kathryn, Roberts, Sheree, Dutton, Emma E., Hunter, Stuart +10 more·2016·Journal of Hepatology
DOI 10.1016/j.jhep.2015.12.017PMC PMC4822535
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Abstract

BACKGROUND & AIMS: 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.

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References 53 · Cited by 212

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  1. [1]Treiner E Duban L Bahram S Radosavljevic M Wanner V Tilloy F Selection of evolutionarily conserved mucosal-associated invariant T cells by MR1 Nature 2003 422 164 169 12634786
  2. [2]Reantragoon R Corbett AJ Sakala IG Gherardin NA Furness JB Chen Z Antigen-loaded MR1 tetramers define T cell receptor heterogeneity in mucosal-associated invariant T cells J Exp Med 2013 210 2305 2320 24101382 PMC3804952
  3. [3]Billerbeck E Kang YH Walker L Lockstone H Grafmueller S Fleming V Analysis of CD161 expression on human CD8+ T cells defines a distinct functional subset with tissue-homing properties ProcNatlAcadSciUSA 2010 107 3006 3011 PMC2840308 20133607
  4. [4]Kang YH Seigel B Bengsch B Fleming VM Billerbeck E Simmons R CD161(+)CD4(+) T cells are enriched in the liver during chronic hepatitis and associated with co-secretion of IL-22 and IFN-gamma Front Immunol 2012 3 346 23181064 PMC3502006
  5. [5]Martin E Treiner E Duban L Guerri L Laude H Toly C Stepwise development of MAIT cells in mouse and human PLoS Biol 2009 7 e54 19278296 PMC2653554
  6. [6]Huang S Gilfillan S Cella M Miley MJ Lantz O Lybarger L Evidence for MR1 antigen presentation to mucosal-associated invariant T cells J Biol Chem 2005 280 21183 21193 15802267
  7. [7]Kjer-Nielsen L Patel O Corbett AJ Le Nours J Meehan B Liu L MR1 presents microbial vitamin B metabolites to MAIT cells Nature 2012 491 717 723 23051753
  8. [8]Ussher JE Klenerman P Willberg CB Mucosal-associated invariant T-cells: new players in anti-bacterial immunity Front Immunol 2014 5 450 25339949 PMC4189401
  9. [9]Meierovics A Yankelevich WJ Cowley SC MAIT cells are critical for optimal mucosal immune responses during in vivo pulmonary bacterial infection Proc Natl Acad Sci U S A 2013 110 E3119 3128 23898209 PMC3746930
  10. [10]Booth JS Salerno-Goncalves R Blanchard TG Patil SA Kader HA Safta AM Mucosal-Associated Invariant T Cells in the Human Gastric Mucosa and Blood: Role in Helicobacter pylori Infection Front Immunol 2015 6 466 26441971 PMC4585133
  11. [11]Kurioka A Ussher JE Cosgrove C Clough C Fergusson JR Smith K MAIT cells are licensed through granzyme exchange to kill bacterially sensitized targets Mucosal Immunol 2014 PMC4288950 25269706
  12. [12]Ussher JE Bilton M Attwod E Shadwell J Richardson R de Lara C CD161++ CD8+ T cells, including the MAIT cell subset, are specifically activated by IL-12+IL-18 in a TCR-independent manner Eur J Immunol 2014 44 195 203 24019201 PMC3947164
  13. [13]Le Bourhis L Martin E Peguillet I Guihot A Froux N Core M Antimicrobial activity of mucosal-associated invariant T cells Nat Immunol 2010 11 701 708 20581831
  14. [14]Oo YH Adams DH The role of chemokines in the recruitment of lymphocytes to the liver JAutoimmun 2010 34 45 54 19744827
  15. [15]Balmer ML Slack E de Gottardi A Lawson MA Hapfelmeier S Miele L The liver may act as a firewall mediating mutualism between the host and its gut commensal microbiota Sci Transl Med 2014 6 237ra266 24848256
  16. [16]Tang XZ Jo J Tan AT Sandalova E Chia A Tan KC IL-7 licenses activation of human liver intrasinusoidal mucosal-associated invariant T cells J Immunol 2013 190 3142 3152 23447689
  17. [17]Hubscher SG Histological grading and staging in chronic hepatitis: clinical applications and problems J Hepatol 1998 29 1015 1022 9875653
  18. [18]Racanelli V Rehermann B The liver as an immunological organ Hepatology 2006 43 S54 S62 16447271
  19. [19]Schrumpf E Tan C Karlsen TH Sponheim J Bjorkstrom NK Sundnes O The Biliary Epithelium Presents Antigens to and Activates Natural Killer T Cells Hepatology 2015 PMC4589438 25855031
  20. [20]Le Bourhis L Dusseaux M Bohineust A Bessoles S Martin E Premel V MAIT cells detect and efficiently lyse bacterially-infected epithelial cells PLoS Pathog 2013 9 e1003681 24130485 PMC3795036
  21. [21]Oo YH Banz V Kavanagh D Liaskou E Withers DR Humphreys E CXCR3-dependent recruitment and CCR6-mediated positioning of Th-17 cells in the inflamed liver J Hepatol 2012 57 1044 1051 22796894 PMC3994510
  22. [22]Miley MJ Truscott SM Yu YY Gilfillan S Fremont DH Hansen TH Biochemical features of the MHC-related protein 1 consistent with an immunological function J Immunol 2003 170 6090 6098 12794138
  23. [23]Heydtmann M Lalor PF Eksteen JA Hubscher SG Briskin M Adams DH CXC chemokine ligand 16 promotes integrin-mediated adhesion of liver-infiltrating lymphocytes to cholangiocytes and hepatocytes within the inflamed human liver JImmunol 2005 174 1055 1062 15634930
  24. [24]Grant AJ Lalor PF Salmi M Jalkanen S Adams DH Homing of mucosal lymphocytes to the liver in the pathogenesis of hepatic complications of inflammatory bowel disease Lancet 2002 359 150 157 11809275
  25. [25]Curbishley SM Eksteen B Gladue RP Lalor P Adams DH CXCR3 Activation Promotes Lymphocyte Transendothelial Migration across Human Hepatic Endothelium under Fluid Flow Am J Pathol 2005 167 887 899 16127166 PMC1698725
  26. [26]Eksteen B Grant AJ Miles A Curbishley SM Lalor PF Hubscher SG Hepatic endothelial CCL25 mediates the recruitment of CCR9+ gut-homing lymphocytes to the liver in primary sclerosing cholangitis J Exp Med 2004 200 1511 1517 15557349 PMC2211943
  27. [27]Salerno-Goncalves R Rezwan T Sztein MB B cells modulate mucosal associated invariant T cell immune responses Front Immunol 2014 4 511 24432025 PMC3882667
  28. [28]Le Bourhis L Mburu YK Lantz O MAIT cells, surveyors of a new class of antigen: development and functions Curr Opin Immunol 2013 25 174 180 23422835
  29. [29]Serriari NE Eoche M Lamotte L Lion J Fumery M Marcelo P Innate mucosal-associated invariant T (MAIT) cells are activated in inflammatory bowel diseases Clin Exp Immunol 2014 176 266 274 24450998 PMC3992039
  30. [30]Lalor PF Adams DH Adhesion of lymphocytes to hepatic endothelium MolPathol 1999 52 214 219 PMC395702 10694942
  31. [31]Lalor PF Clements JM Pigott R Humphries MJ Spragg JH Nash GB Association between receptor density, cellular activation, and transformation of adhesive behavior of flowing lymphocytes binding to VCAM-1 EurJImmunol 1997 27 1422 1426 9209494
  32. [32]Willing A Leach OA Ufer F Attfield KE Steinbach K Kursawe N CD8(+) MAIT cells infiltrate into the CNS and alterations in their blood frequencies correlate with IL-18 serum levels in multiple sclerosis Eur J Immunol 2014 44 3119 3128 25043505
  33. [33]Alabraba EB Lai V Boon L Wigmore SJ Adams DH Afford SC Coculture of human liver macrophages and cholangiocytes leads to CD40-dependent apoptosis and cytokine secretion Hepatology 2007 17999420
  34. [34]Ikeda A Aoki N Kido M Iwamoto S Nishiura H Maruoka R Progression of autoimmune hepatitis is mediated by IL-18-producing dendritic cells and hepatic CXCL9 expression in mice Hepatology 2014 60 224 236 24700550
  35. [35]Grant AJ Lalor PF Hubscher SG Briskin M Adams DH MAdCAM-1 expressed in chronic inflammatory liver disease supports mucosal lymphocyte adhesion to hepatic endothelium (MAdCAM-1 in chronic inflammatory liver disease) Hepatology 2001 33 1065 1072 11343233
  36. [36]Eksteen B Miles A Curbishley SM Tselepis C Grant AJ Walker LS Epithelial Inflammation Is Associated with CCL28 Production and the Recruitment of Regulatory T Cells Expressing CCR10 JImmunol 2006 177 593 603 16785557
  37. [37]Shields PL Morland CM Salmon M Qin S Hubscher SG Adams DH Chemokine and chemokine receptor interactions provide a mechanism for selective T cell recruitment to specific liver compartments within hepatitis C-infected liver JImmunol 1999 163 6236 6243 10570316
  38. [38]Afford SC Humphreys EH Reid DT Russell CL Banz VM Oo Y Vascular cell adhesion molecule 1 expression by biliary epithelium promotes persistence of inflammation by inhibiting effector T-cell apoptosis Hepatology 2014 59 1932 1943 24338559
  39. [39]Dusseaux M Martin E Serriari N Peguillet I Premel V Louis D Human MAIT cells are xenobiotic-resistant, tissue-targeted, CD161hi IL-17-secreting T cells Blood 2011 117 1250 1259 21084709
  40. [40]Sundstrom P Ahlmanner F Akeus P Sundquist M Alsen S Yrlid U Human Mucosa-Associated Invariant T Cells Accumulate in Colon Adenocarcinomas but Produce Reduced Amounts of IFN-gamma J Immunol 2015 195 3472 3481 26297765
  41. [41]Hirschfield GM Karlsen TH Lindor KD Adams DH Primary sclerosing cholangitis Lancet 2013 382 1587 1599 23810223
  42. [42]Wigg AJ Gunson BK Mutimer DJ Outcomes following liver transplantation for seronegative acute liver failure: experience during a 12-year period with more than 100 patients Liver Transpl 2005 11 27 34 15690533
  43. [43]Sharma PK Wong EB Napier RJ Bishai WR Ndung'u T Kasprowicz VO High expression of CD26 accurately identifies human bacteria-reactive MR1-restricted MAIT cells Immunology 2015 PMC4479542 25752900
  44. [44]Deaglio S Dwyer KM Gao W Friedman D Usheva A Erat A Adenosine generation catalyzed by CD39 and CD73 expressed on regulatory T cells mediates immune suppression J Exp Med 2007 204 1257 1265 17502665 PMC2118603
  45. [45]Ma HD Wang YH Chang C Gershwin ME Lian ZX The intestinal microbiota and microenvironment in liver Autoimmun Rev 2015 14 183 191 25315744
  46. [46]Rong GH Yang GX Ando Y Zhang W He XS Leung PS Human intrahepatic biliary epithelial cells engulf blebs from their apoptotic peers Clin Exp Immunol 2013 172 95 103 23480189 PMC3719935
  47. [47]Harada K Shimoda S Sato Y Isse K Ikeda H Nakanuma Y Periductal interleukin-17 production in association with biliary innate immunity contributes to the pathogenesis of cholangiopathy in primary biliary cirrhosis ClinExpImmunol 2009 157 261 270 PMC2730852 19604266
  48. [48]Afford SC Rhandawa S Eliopoulos AG Hubscher SG Young LS Adams DH CD40 activation induces apoptosis in cultured human hepatocytes via induction of cell surface FasL expression and amplifies Fas mediated hepatocyte death during allograft rejection J Exp Med 1999 189 441 446 9892626 PMC2192998
  49. [49]Humphreys EH Williams KT Adams DH Afford SC Primary and malignant cholangiocytes undergo CD40 mediated Fas dependent apoptosis, but are insensitive to direct activation with exogenous Fas ligand PLoS One 2010 5 e14037 21103345 PMC2984448
  50. [50]Walker LJ Kang YH Smith MO Tharmalingham H Ramamurthy N Fleming VM Human MAIT and CD8alphaalpha cells develop from a pool of type-17 precommitted CD8+ T cells Blood 2012 119 422 433 22086415 PMC3257008
  51. [51]Fergusson JR Smith KE Fleming VM Rajoriya N Newell EW Simmons R CD161 Defines a Transcriptional and Functional Phenotype across Distinct Human T Cell Lineages Cell Rep 2014 9 1075 1088 25437561 PMC4250839

Authors
Jeffery, H. C., van Wilgenburg, B., Kurioka, A., Parekh, K., Stirling, K., Roberts, S., Dutton, E. E., Hunter, S., Geh, D., Braitch, M. K., Rajanayagam, J., Iqbal, T., Pinkney, T., Brown, R., Withers, D. R., Adams, D. H., Klenerman, P., & Oo, Y. H.
Affiliations
  • University of Birmingham (GB)
  • University of Oxford (GB)
  • University Hospitals Birmingham NHS Foundation Trust (GB)
Corresponding author
Oo, Ye H.
ORCID
Venue
Journal of Hepatology
Publisher
Elsevier BV
Published
2016-05
Volume
64
Issue
5
Pages
1118-1127
ISSN
0168-8278 (ISSN-L)
DOI
10.1016/j.jhep.2015.12.017
PMC
PMC4822535
OpenAlex
W2288573834
Cited by
212
References
53
Citations by year
2026: 11 · 2025: 15 · 2024: 17 · 2023: 16 · 2022: 26 · 2021: 17 · 2020: 34 · 2019: 20 · 2018: 27 · 2017: 18 · 2016: 10
FWCI
10.87
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Hepatology (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • University of Birmingham Research Portal (University of Birmingham) (submittedVersion, cc-by)
Funders
  • Wellcome Trust (WT091663MA, 091663, 109965/Z/15/Z, 110199/Z/15/Z)
  • Queen Elizabeth Hospital Birmingham Charity
  • National Institute for Health and Care Research (NF-SI-0512-10080, NF-SI-0515-10005, NF-SI-0510-10204)
  • Bowel Disease Research Foundation
  • National Institutes of Health
  • Medical Research Council (G1002552, MC_PC_12020)
  • Biotechnology and Biological Sciences Research Council (1511338)
  • National Institute of Allergy and Infectious Diseases (U19AI082630)
Topics
  • Health Sciences › Medicine › Hepatology › Liver Diseases and Immunity
  • Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
  • Health Sciences › Medicine › Surgery › Pediatric Hepatobiliary Diseases and Treatments
Keywords
mucosal-associated invariant T cells, MR1, biliary epithelium, Escherichia coli, macrophages, chemokine receptors, acute liver failure, interferon-gamma, CD40 ligand, Th1/Th17 differentiation, biliary tract diseases
MeSH terms
Mucosal-Associated Invariant T Cells, B-Lymphocytes, Bile Ducts, Intrahepatic, Escherichia coli, Humans, Immunity, Innate, Liver, Lymphocyte Activation, T-Lymphocyte Subsets

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