Aoife Kelly1, Ronan Fahey1, Jean M Fletcher2, Catherine Keogh1, Anne G Carroll3, Ravichand Siddachari3, Justin Geoghegan3, John E Hegarty4, Elizabeth J Ryan5, Cliona O'Farrelly6. 1. School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland. 2. School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland; School of Medicine, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland. 3. Department of Surgery, St. Vincent's University Hospital, Dublin 4, Ireland. 4. Liver Unit, St. Vincent's University Hospital, Dublin 4, Ireland. 5. Centre for Colorectal Disease, Education and Research Centre, St. Vincent's University Hospital, Dublin 4, Ireland; School of Medicine and Medical Sciences, University College Dublin, Dublin 4, Ireland. 6. School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland; School of Medicine, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland. Electronic address: cliona.ofarrelly@tcd.ie.
Abstract
BACKGROUND & AIMS: Extensive populations of liver immune cells detect and respond to homeostatic perturbation caused by damage, infection or malignancy. Dendritic cells (DCs) are central to these activities, governing the balance between tolerance and immunity. Most of our knowledge about human liver DCs is derived from studies on peritumoral tissue. Little is known about the phenotype and function of DCs, in particular the recently described CD141(+) subset, in healthy human liver and how this profile is altered in liver disease. METHODS: During liver transplantation, healthy donor and diseased explant livers were perfused and hepatic mononuclear cells isolated. Dendritic cell subset frequency and phenotype were characterised in liver perfusates by flow cytometry and the function of CD141(+) DCs was evaluated by mixed lymphocyte reactions (MLRs) and measuring cytokine secretion. RESULTS: Almost one third of liver CD11c(+) myeloid DCs (mDCs) expressed CD141 compared to <5% of circulating mDCs. Hepatic CD141(+) DCs demonstrated pro-inflammatory function in allogeneic MLRs, inducing T cell production of interferon gamma (IFN-γ) and interleukin (IL)-17. While CD123(+) plasmacytoid DCs (pDCs) and CD1c(+) mDCs were expanded in diseased liver perfusates, CD141(+) DCs were significantly depleted. Despite their depletion, CD141(+) DCs from explant livers produced markedly increased poly(I:C)-induced IFN lambda (IFN-λ) compared with donor DCs. CONCLUSIONS: Accumulation of CD141(+) DCs in healthy liver, which are significantly depleted in liver disease, suggests differential involvement of mDC subsets in liver immunity.
BACKGROUND & AIMS: Extensive populations of liver immune cells detect and respond to homeostatic perturbation caused by damage, infection or malignancy. Dendritic cells (DCs) are central to these activities, governing the balance between tolerance and immunity. Most of our knowledge about human liver DCs is derived from studies on peritumoral tissue. Little is known about the phenotype and function of DCs, in particular the recently described CD141(+) subset, in healthy human liver and how this profile is altered in liver disease. METHODS: During liver transplantation, healthy donor and diseased explant livers were perfused and hepatic mononuclear cells isolated. Dendritic cell subset frequency and phenotype were characterised in liver perfusates by flow cytometry and the function of CD141(+) DCs was evaluated by mixed lymphocyte reactions (MLRs) and measuring cytokine secretion. RESULTS: Almost one third of liver CD11c(+) myeloid DCs (mDCs) expressed CD141 compared to <5% of circulating mDCs. Hepatic CD141(+) DCs demonstrated pro-inflammatory function in allogeneic MLRs, inducing T cell production of interferon gamma (IFN-γ) and interleukin (IL)-17. While CD123(+) plasmacytoid DCs (pDCs) and CD1c(+) mDCs were expanded in diseased liver perfusates, CD141(+) DCs were significantly depleted. Despite their depletion, CD141(+) DCs from explant livers produced markedly increased poly(I:C)-induced IFN lambda (IFN-λ) compared with donor DCs. CONCLUSIONS: Accumulation of CD141(+) DCs in healthy liver, which are significantly depleted in liver disease, suggests differential involvement of mDC subsets in liver immunity.
Authors: Mary Canavan; Alice M Walsh; Vipul Bhargava; Sarah M Wade; Trudy McGarry; Viviana Marzaioli; Barry Moran; Monika Biniecka; Hannah Convery; Siobhan Wade; Carl Orr; Ronan Mullan; Jean M Fletcher; Sunil Nagpal; Douglas J Veale; Ursula Fearon Journal: JCI Insight Date: 2018-12-06
Authors: Joel T Haas; Luisa Vonghia; Denis A Mogilenko; An Verrijken; Olivier Molendi-Coste; Sébastien Fleury; Audrey Deprince; Artemii Nikitin; Eloïse Woitrain; Lucie Ducrocq-Geoffroy; Samuel Pic; Bruno Derudas; Hélène Dehondt; Céline Gheeraert; Luc Van Gaal; Ann Driessen; Philippe Lefebvre; Bart Staels; Sven Francque; David Dombrowicz Journal: Nat Metab Date: 2019-06-14
Authors: Aoife Kelly; Mark W Robinson; Gerard Roche; Christine A Biron; Cliona O'Farrelly; Elizabeth J Ryan Journal: J Interferon Cytokine Res Date: 2016-09-12 Impact factor: 2.607
Authors: Victoria M Velazquez; Luke S Uebelhoer; Manoj Thapa; Chris C Ibegbu; Cynthia Courtney; Steven E Bosinger; Joseph F Magliocca; Andrew B Adams; Allan D Kirk; Stuart J Knechtle; Daniel Kalman; Mehul S Suthar; Arash Grakoui Journal: Hepatology Date: 2015-01-30 Impact factor: 17.425
Authors: A Podhorzer; N Paladino; M L Cuarterolo; H A Fainboim; S Paz; G Theiler; M Capucchio; S I López; A Machicote; S Montal; G Podesta; L Fainboim Journal: Genes Immun Date: 2016-02-18 Impact factor: 2.676