Increased sensitivity of Treg cells from patients with PBC to low dose IL-12 drives their differentiation into IFN-γ secreting cells

Research output: Contribution to journalArticle

Authors

  • Samita Patel
  • Danai Bagkou DImakou
  • Sarah Akiror
  • Mahesh Krishna
  • George F Mells
  • David Jones
  • SJ Bowman
  • Gideon M Hirschfield

External organisations

  • Institute of Immunology & Immunotherapy, College of Medical & Dental Sciences, University of Birmingham, Birmingham B15 2TT, UK
  • Weiss School of Natural Sciences, Rice University, Houston, Texas
  • University of Cambridge
  • Newcastle University
  • Institute of Inflammation and Ageing, University of Birmingham, England, UK.
  • NIHR Birmingham Biomedical Research Centre, University of Birmingham and University Hospitals Birmingham NHS Foundation Trust
  • Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham B15 2TT, United Kingdom.
  • Toronto Centre for Liver Disease, University Health Network, University of Toronto

Abstract

IL-12 is a pro-inflammatory cytokine that induces the production of interferon-γ (IFNγ) and favours the differentiation of T helper 1 (Th1) cells. In the presence of IL-12 human Treg cells acquire a Th1-like phenotype with reduced suppressive activity in vitro. Primary biliary cholangitis (PBC) is an autoimmune cholestatic liver disease characterised by high Th1 and Th17 infiltrating cells, reduced frequencies of Treg cells, and a genetic association with IL-12 signalling. Herein, we sought to evaluate the IL-12 signalling pathway in PBC pathology, by studying human samples from patients with PBC, alongside those with primary Sjögren’s syndrome (pSS)(autoimmune disease with IL-12 signalling gene association), primary sclerosing cholangitis (PSC) (cholestatic liver disease without IL-12 gene association) and healthy individuals. Our data revealed that TLR stimulation of PBC (n=17) and pSSmonocytes (n=6) resulted in significant induction of IL12A mRNA (p<0.05, p<0.01, respectively) compared to PSC monocytes (n=13) and at similar levels to HC monocytes (n=8). PSC monocytes expressed significantly less IL-12p70 (108pg/ml, mean) and IL-23 (358pg/ml) compared to HC (458pg/ml and 951pg/ml, respectively) (p<0.01, p<0.05). Treg cells from patients with PBC (n=16) and pSS (n=3) but not PSC (n=10) and HC (n=8) responded to low dose (10ng/ml) IL-12 stimulation by significant upregulation of IFNγ (55 and 186pg/ml, respectively) compared to PSC Treg cells (6pg/ml)(p<0.05). This effect was mediated by the rapid and strong phosphorylation of STAT4 on Treg cells from patients with PBC and pSS (p<0.05) but not PSC and HC. In the liver of patients with PBC (n=7) a significantly higher proportion of IL-12Rβ2+Tregs (16% on average) was detected (p<0.05) compared to other liver disease controls (5%)(n=18) which also showed ex vivo high IFNG and TBET expression. CONCLUSION: Our data show an increased sensitivity of PBC and pSS Treg cells to low dose IL-12 stimulation, providing ongoing support for the importance of the IL12-IL-12Rβ2-STAT4 pathway on Treg cells in disease pathogenesis and potentially treatment.

Bibliographic note

Address for correspondence: Professor G M Hirschfield, Toronto Centre for Liver Disease Toronto General Hospital 9EB-226 University Health Network Toronto, ON, Canada Email: gideon.hirschfield@uhn.ca Note also that Evaggalia Liaskou is soon to go onto maternity leave in case there are any queries regarding this publication.

Details

Original languageEnglish
Pages (from-to)143-155
JournalJournal of Autoimmunity
Volume94
Early online date14 Aug 2018
Publication statusPublished - Nov 2018

Keywords

  • Primary biliary cholangitis, primary sclerosing cholangitis, primary Sjögren’s syndrome, autoimmunity, T regulatory cells, Th1 cells

ASJC Scopus subject areas