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

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• 作者：Hannah C. Jeffery¹ ; ^&dagger ; ; Bonnie van Wilgenburg² ; ^&dagger ; ; Ayako Kurioka² ; Krishan Parekh¹ ; Kathryn Stirling¹ ; Sheree Roberts¹ ; Emma E. Dutton³ ; Stuart Hunter¹ ; Daniel Geh¹ ; Manjit K. Braitch¹ ; Jeremy Rajanayagam¹ ; Tariq Iqbal⁴ ; Thomas Pinkney⁴ ; Rachel Brown⁴ ; David R. Withers³ ; David H. Adams¹ ; ⁴ ; Paul Klenerman² ; ^&Dagger ; ; Ye H. Oo¹ ; ⁴ ; ^&Dagger ; ; ^{y.h.oo@bham.ac.uk" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Human liver ; Mucosal-associated invariant T cells ; Biliary epithelium ; E. coli ; Immune response ; Biliary firewall
• 刊名：Journal of Hepatology
• 出版年：2016
• 出版时间：May 2016
• 年：2016
• 卷：64
• 期：5
• 页码：1118-1127
• 全文大小：2853 K

文摘

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.