Changes in natural killer cells and exhausted memory regulatory T Cells with corticosteroid therapy in acute autoimmune hepatitis

Research output: Contribution to journalArticle

Authors

  • Manjit K. Braitch
  • Chris Bagnall
  • James Hodson
  • Rebecca E. Wawman
  • Lin Lee Wong
  • Helen Bartlett
  • Ansgar W. Lohse
  • Jessica Dyson
  • David Jones
  • Paul Klenerman
  • David Adams
  • Ye Htun Oo

External organisations

  • Centre for Liver Research, Institute of Immunology and Immunotherapy and National Institute of Health Research Inflammation Biomedical Research Centre Birmingham; University of Birmingham; Birmingham United Kingdom
  • Institute of Translational Medicine; University Hospitals Birmingham National Health Services Foundation Trust, University of Birmingham; Birmingham United Kingdom
  • School of Life Sciences, Faculty of Health and Life Sciences, Coventry University, Coventry, United Kingdom.
  • Newcastle University
  • Department of Clinical Immunology, University of Birmingham, Birmingham, United Kingdom.
  • University of Hamburg Medical institutions UKE, Hamburg, Germany.
  • Liver Transplantation and Hepatobiliary Unit, Queen Elizabeth Hospital; University Hospitals Birmingham National Health Service Foundation Trust; Birmingham United Kingdom
  • Department of Histopathology, Queen Elizabeth Hospital; University Hospitals Birmingham National Health Service Foundation Trust; Birmingham United Kingdom
  • Peter Medawar Building for Pathogen Research, University of Oxford, Oxford, United Kingdom.

Abstract

Autoimmune hepatitis (AIH) is an immune‐mediated liver disease currently treated by immunosuppressive medications with significant side effects. Thus, novel mechanistic treatments are greatly needed. We performed prospective deep immunophenotyping of blood immune cells in patients with acute AIH before and after corticosteroid therapy. Blood samples from 26 patients with acute AIH (United Kingdom‐AIH Consortium) were phenotyped by flow cytometry at baseline and 4 months after starting corticosteroids. Pretreatment liver tissues were stained for forkhead box P3‐positive (FOXP3POS) regulatory T cells (Tregs), clusters of differentiation (CD)56POS natural killer (NK) cells, and chemokine (C‐X‐C motif) ligand 10. Chemokine secretion by cultured primary hepatocyte and biliary epithelial cells was measured by enzyme‐linked immunosorbent assay. Functional coculture assays with stimulated NK cells and Tregs were performed. CD161 ligand, lectin‐like transcript‐1 expression by intrahepatic immune cells was demonstrated with flow cytometry. Frequencies of NKbright cells declined with therapy (P < 0.001) and correlated with levels of alanine aminotransferase (P = 0.023). The Treg:NKbright ratio was lower pretreatment, and Tregs had an activated memory phenotype with high levels of CD39, cytotoxic T lymphocyte antigen 4, and FOXP3 but also high programmed death ligand 1, indicating exhaustion. Coculture experiments suggested the Tregs could not efficiently suppress interferon‐γ secretion by NK cells. Both Tregs and NK cells had high expression of liver infiltration and T helper 17 plasticity‐associated marker CD161 (P = 0.04). Pretreatment and CD161pos NK cells expressed high levels of perforin and granzyme B, consistent with an activated effector phenotype (P < 0.05). Lectin‐like transcript 1, a ligand for CD161, is expressed on intrahepatic B cells, monocytes, and neutrophils. Conclusion: Activated effector NK cells, which correlate with biochemical measurements of hepatitis, and exhausted memory Tregs are increased in the blood of patients with treatment‐naive AIH and decline with corticosteroid therapy. Inadequate regulation of NK cells by exhausted FOXP3pos Tregs may play a role in AIH pathogenesis and contribute to liver injury. (Hepatology Communications 2018;2:421‐436)

Details

Original languageEnglish
Pages (from-to)421-436
JournalHepatology Communications
Volume2
Issue number4
Early online date26 Feb 2018
Publication statusPublished - 1 Apr 2018