Evaggelia Liaskou1, Louisa E Jeffery2, Palak J Trivedi1, Gary M Reynolds1, Shankar Suresh1, Tony Bruns3, David H Adams1, David M Sansom4, Gideon M Hirschfield5. 1. Centre for Liver Research and National Institute for Health Research Biomedical Research Unit in Liver Disease, Institute of Biomedical Research, University of Birmingham, Birmingham, United Kingdom. 2. Medical Research Council Centre for Immune Regulation, School of Immunity and Infection, Institute of Biomedical Research, University of Birmingham, Birmingham, United Kingdom. 3. Centre for Liver Research and National Institute for Health Research Biomedical Research Unit in Liver Disease, Institute of Biomedical Research, University of Birmingham, Birmingham, United Kingdom; Department of Internal Medicine IV, Gastroenterology, Hepatology and Infectious Disease, Jena University Hospital, Friedrich Schiller University of Jena, Jena, Germany; Center for Sepsis Control and Care, Jena University Hospital, Friedrich Schiller University of Jena, Jena, Germany. 4. Medical Research Council Centre for Immune Regulation, School of Immunity and Infection, Institute of Biomedical Research, University of Birmingham, Birmingham, United Kingdom; Institute for Immunity and Transplantation, University College London, Royal Free Campus, London, United Kingdom. 5. Centre for Liver Research and National Institute for Health Research Biomedical Research Unit in Liver Disease, Institute of Biomedical Research, University of Birmingham, Birmingham, United Kingdom. Electronic address: g.hirschfield@bham.ac.uk.
Abstract
BACKGROUND & AIMS: T-cell-mediated biliary injury is a feature of primary sclerosing cholangitis (PSC). We studied the roles of CD28(-) T cells in PSC and their regulation by vitamin D. METHODS: Peripheral and liver-infiltrating mononuclear cells were isolated from blood or fresh liver tissue. We analyzed numbers, phenotypes, functions, and localization patterns of CD28(-) T cells, along with their ability to activate biliary epithelial cells. We measured levels of tumor necrosis factor (TNF)α in liver tissues from patients with PSC and the effects of exposure to active vitamin D (1,25[OH]2D3) on expression of CD28. RESULTS: A significantly greater proportion of CD4(+) and CD8(+) T cells that infiltrated liver tissues of patients with PSC were CD28(-), compared with control liver tissue (CD4(+): 30.3% vs 2.5%, P < .0001; and CD8(+): 68.5% vs 31.9%, P < .05). The mean percentage of CD4(+)CD28(-) T cells in liver tissues from patients with PSC was significantly higher than from patients with primary biliary cirrhosis or nonalcoholic steatohepatitis (P < .05). CD28(-) T cells were activated CD69(+)CD45RA(-) C-C chemokine receptor (CCR)7(-) effector memory and perforin(+) granzyme B(+) cytotoxic cells, which express CD11a, CX3CR1, C-X3-C motif receptor 6 (CXCR6), and CCR10-consistent with their infiltration of liver and localization around bile ducts. Compared with CD28(+) T cells, activated CD28(-) T cells produced significantly higher levels of interferon γ and TNFα (P < .05), and induced up-regulation of intercellular cell adhesion molecule-1, HLA-DR, and CD40 by primary epithelial cells (3.6-fold, 1.5-fold, and 1.2-fold, respectively). Liver tissue from patients with PSC contained high levels of TNFα; TNFα down-regulated the expression of CD28 by T cells in vitro (P < .01); this effect was prevented by administration of 1,25(OH)2D3 (P < .05). CONCLUSIONS: Inflammatory CD28(-) T cells accumulate in livers of patients with PSC and localize around bile ducts. The TNFα-rich microenvironment of this tissue promotes inflammation; these effects are reversed by vitamin D in vitro.
BACKGROUND & AIMS: T-cell-mediated biliary injury is a feature of primary sclerosing cholangitis (PSC). We studied the roles of CD28(-) T cells in PSC and their regulation by vitamin D. METHODS: Peripheral and liver-infiltrating mononuclear cells were isolated from blood or fresh liver tissue. We analyzed numbers, phenotypes, functions, and localization patterns of CD28(-) T cells, along with their ability to activate biliary epithelial cells. We measured levels of tumor necrosis factor (TNF)α in liver tissues from patients with PSC and the effects of exposure to active vitamin D (1,25[OH]2D3) on expression of CD28. RESULTS: A significantly greater proportion of CD4(+) and CD8(+) T cells that infiltrated liver tissues of patients with PSC were CD28(-), compared with control liver tissue (CD4(+): 30.3% vs 2.5%, P < .0001; and CD8(+): 68.5% vs 31.9%, P < .05). The mean percentage of CD4(+)CD28(-) T cells in liver tissues from patients with PSC was significantly higher than from patients with primary biliary cirrhosis or nonalcoholic steatohepatitis (P < .05). CD28(-) T cells were activated CD69(+)CD45RA(-) C-C chemokine receptor (CCR)7(-) effector memory and perforin(+) granzyme B(+) cytotoxic cells, which express CD11a, CX3CR1, C-X3-C motif receptor 6 (CXCR6), and CCR10-consistent with their infiltration of liver and localization around bile ducts. Compared with CD28(+) T cells, activated CD28(-) T cells produced significantly higher levels of interferon γ and TNFα (P < .05), and induced up-regulation of intercellular cell adhesion molecule-1, HLA-DR, and CD40 by primary epithelial cells (3.6-fold, 1.5-fold, and 1.2-fold, respectively). Liver tissue from patients with PSC contained high levels of TNFα; TNFα down-regulated the expression of CD28 by T cells in vitro (P < .01); this effect was prevented by administration of 1,25(OH)2D3 (P < .05). CONCLUSIONS: Inflammatory CD28(-) T cells accumulate in livers of patients with PSC and localize around bile ducts. The TNFα-rich microenvironment of this tissue promotes inflammation; these effects are reversed by vitamin D in vitro.
Authors: Ye H Oo; Chris J Weston; Patricia F Lalor; Stuart M Curbishley; David R Withers; Gary M Reynolds; Shishir Shetty; Jehan Harki; Jean C Shaw; Bertus Eksteen; Stefan G Hubscher; Lucy S K Walker; David H Adams Journal: J Immunol Date: 2010-02-17 Impact factor: 5.422
Authors: Louisa E Jeffery; Fiona Burke; Manuela Mura; Yong Zheng; Omar S Qureshi; Martin Hewison; Lucy S K Walker; David A Lammas; Karim Raza; David M Sansom Journal: J Immunol Date: 2009-11-01 Impact factor: 5.422
Authors: Bertus Eksteen; Alice Miles; Stuart M Curbishley; Chris Tselepis; Allister J Grant; Lucy S K Walker; David H Adams Journal: J Immunol Date: 2006-07-01 Impact factor: 5.422
Authors: Evaggelia Liaskou; Henning W Zimmermann; Ka-Kit Li; Ye H Oo; Shankar Suresh; Zania Stamataki; Omar Qureshi; Patricia F Lalor; Jean Shaw; Wing-kin Syn; Stuart M Curbishley; David H Adams Journal: Hepatology Date: 2012-12-04 Impact factor: 17.425
Authors: Jimmy Z Liu; Johannes Roksund Hov; Trine Folseraas; Eva Ellinghaus; Simon M Rushbrook; Nadezhda T Doncheva; Ole A Andreassen; Rinse K Weersma; Tobias J Weismüller; Bertus Eksteen; Pietro Invernizzi; Gideon M Hirschfield; Daniel Nils Gotthardt; Albert Pares; David Ellinghaus; Tejas Shah; Brian D Juran; Piotr Milkiewicz; Christian Rust; Christoph Schramm; Tobias Müller; Brijesh Srivastava; Georgios Dalekos; Markus M Nöthen; Stefan Herms; Juliane Winkelmann; Mitja Mitrovic; Felix Braun; Cyriel Y Ponsioen; Peter J P Croucher; Martina Sterneck; Andreas Teufel; Andrew L Mason; Janna Saarela; Virpi Leppa; Ruslan Dorfman; Domenico Alvaro; Annarosa Floreani; Suna Onengut-Gumuscu; Stephen S Rich; Wesley K Thompson; Andrew J Schork; Sigrid Næss; Ingo Thomsen; Gabriele Mayr; Inke R König; Kristian Hveem; Isabelle Cleynen; Javier Gutierrez-Achury; Isis Ricaño-Ponce; David van Heel; Einar Björnsson; Richard N Sandford; Peter R Durie; Espen Melum; Morten H Vatn; Mark S Silverberg; Richard H Duerr; Leonid Padyukov; Stephan Brand; Miquel Sans; Vito Annese; Jean-Paul Achkar; Kirsten Muri Boberg; Hanns-Ulrich Marschall; Olivier Chazouillères; Christopher L Bowlus; Cisca Wijmenga; Erik Schrumpf; Severine Vermeire; Mario Albrecht; John D Rioux; Graeme Alexander; Annika Bergquist; Judy Cho; Stefan Schreiber; Michael P Manns; Martti Färkkilä; Anders M Dale; Roger W Chapman; Konstantinos N Lazaridis; Andre Franke; Carl A Anderson; Tom H Karlsen Journal: Nat Genet Date: 2013-04-21 Impact factor: 38.330
Authors: Angela C Cheung; Maria J Lorenzo Pisarello; Nicholas F LaRusso Journal: Biochim Biophys Acta Mol Basis Dis Date: 2017-07-15 Impact factor: 5.187
Authors: Marcio Francisco Lehmann; Ana Paula Kallaur; Sayonara Rangel Oliveira; Daniela Frizon Alfieri; Franciele Delongui; Johnathan de Sousa Parreira; Maria Caroline Martins de Araújo; Carolina Rossato; Jéssica Tavares de Almeida; Larissa Moliterno Pelegrino; Erick Frank Bragato; Ana Lucia Cruz Fürstenberger Lehmann; Helena Kaminami Morimoto; Marcell Alysson Batisti Lozovoy; Andrea Name Colado Simão; Damácio Ramon Kaimen-Maciel; Edna Maria Vissoci Reiche Journal: Metab Brain Dis Date: 2015-09-11 Impact factor: 3.584
Authors: Amy E Taylor; Alexandra N Carey; Ramesh Kudira; Celine S Lages; Tiffany Shi; Simon Lam; Rebekah Karns; Julia Simmons; Kumar Shanmukhappa; Maha Almanan; Claire A Chougnet; Alexander G Miethke Journal: Hepatology Date: 2018-09-30 Impact factor: 17.425