Open AccessChanges in natural killer cells and exhausted memory regulatory T Cells with corticosteroid therapy in acute autoimmune hepatitis
Author(s) -
Jeffery Hannah C.,
Braitch Manjit K.,
Bagnall Chris,
Hodson James,
Jeffery Louisa E.,
Wawman Rebecca E.,
Wong Lin Lee,
Birtwistle Jane,
Bartlett Helen,
Lohse Ansgar W.,
Hirschfield Gideon M.,
Dyson Jessica,
Jones David,
Hubscher Stefan G.,
Klenerman Paul,
Adams David H.,
Oo Ye H.
Publication year - 2018
Publication title -
hepatology communications
Language(s) - English
Resource type - Journals
ISSN - 2471-254X
DOI - 10.1002/hep4.1163
Subject(s) - autoimmune hepatitis , foxp3 , immunology , granzyme b , immune system , cytotoxic t cell , biology , cxcr3 , perforin , interleukin 21 , immunophenotyping , chemokine , flow cytometry , hepatitis , t cell , chemokine receptor , cd8 , in vitro , biochemistry
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 (FOXP3 POS ) regulatory T cells (Tregs), clusters of differentiation (CD)56 POS 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 NK bright cells declined with therapy ( P < 0.001) and correlated with levels of alanine aminotransferase ( P = 0.023). The Treg:NK bright 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 CD161 pos 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 FOXP3 pos Tregs may play a role in AIH pathogenesis and contribute to liver injury. ( Hepatology Communications 2018;2:421‐436)