PDL1 is expressed in the islets of people with type 1 diabetes and is up-regulated by interferons-α and-γ via IRF1 inductionResearch in context
Maikel L. Colli,
Jessica L.E. Hill,
Laura Marroquí,
Jessica Chaffey,
Reinaldo S. Dos Santos,
Pia Leete,
Alexandra Coomans de Brachène,
Flavia M.M. Paula,
Anne Op de Beeck,
Angela Castela,
Lorella Marselli,
Lars Krogvold,
Knut Dahl-Jorgensen,
Piero Marchetti,
Noel G. Morgan,
Sarah J. Richardson,
Décio L. Eizirik
Affiliations
Maikel L. Colli
ULB Center for Diabetes Research, Medical Faculty, Université Libre de Bruxelles, Brussels 1070, Belgium; Corresponding authors at: ULB Center for Diabetes Research, Medical Faculty, Université Libre de Bruxelles, Brussels 1070, Belgium.
Jessica L.E. Hill
Institute of Biomedical & Clinical Science, University of Exeter Medical School, Exeter EX2 5DW, UK
Laura Marroquí
ULB Center for Diabetes Research, Medical Faculty, Université Libre de Bruxelles, Brussels 1070, Belgium
Jessica Chaffey
Institute of Biomedical & Clinical Science, University of Exeter Medical School, Exeter EX2 5DW, UK
Reinaldo S. Dos Santos
ULB Center for Diabetes Research, Medical Faculty, Université Libre de Bruxelles, Brussels 1070, Belgium
Pia Leete
Institute of Biomedical & Clinical Science, University of Exeter Medical School, Exeter EX2 5DW, UK
Alexandra Coomans de Brachène
ULB Center for Diabetes Research, Medical Faculty, Université Libre de Bruxelles, Brussels 1070, Belgium
Flavia M.M. Paula
ULB Center for Diabetes Research, Medical Faculty, Université Libre de Bruxelles, Brussels 1070, Belgium
Anne Op de Beeck
ULB Center for Diabetes Research, Medical Faculty, Université Libre de Bruxelles, Brussels 1070, Belgium
Angela Castela
ULB Center for Diabetes Research, Medical Faculty, Université Libre de Bruxelles, Brussels 1070, Belgium
Lorella Marselli
Department of Clinical and Experimental Medicine, Islet Cell Laboratory, University of Pisa, 56126 Pisa, Italy
Lars Krogvold
Division of Paediatric and Adolescent Medicine, Oslo University Hospital, Oslo, Norway
Knut Dahl-Jorgensen
Division of Paediatric and Adolescent Medicine, Oslo University Hospital, Oslo, Norway
Piero Marchetti
Department of Clinical and Experimental Medicine, Islet Cell Laboratory, University of Pisa, 56126 Pisa, Italy
Noel G. Morgan
Institute of Biomedical & Clinical Science, University of Exeter Medical School, Exeter EX2 5DW, UK
Sarah J. Richardson
Institute of Biomedical & Clinical Science, University of Exeter Medical School, Exeter EX2 5DW, UK
Décio L. Eizirik
ULB Center for Diabetes Research, Medical Faculty, Université Libre de Bruxelles, Brussels 1070, Belgium; Corresponding authors at: ULB Center for Diabetes Research, Medical Faculty, Université Libre de Bruxelles, Brussels 1070, Belgium.
Background: Antibodies targeting PD-1 and its ligand PDL1 are used in cancer immunotherapy but may lead to autoimmune diseases, including type 1 diabetes (T1D). It remains unclear whether PDL1 is expressed in pancreatic islets of people with T1D and how is it regulated. Methods: The expression of PDL1, IRF1, insulin and glucagon was evaluated in samples of T1D donors by immunofluorescence. Cytokine-induced PDL1 expression in the human beta cell line, EndoC-βH1, and in primary human pancreatic islets was determined by real-time RT-PCR, flow cytometry and Western blot. Specific and previously validated small interference RNAs were used to inhibit STAT1, STAT2, IRF1 and JAK1 signaling. Key results were validated using the JAK inhibitor Ruxolitinib. Findings: PDL1 was present in insulin-positive cells from twelve T1D individuals (6 living and 6 deceased donors) but absent from insulin-deficient islets or from the islets of six non-diabetic controls. Interferons-α and -γ, but not interleukin-1β, induced PDL1 expression in vitro in human islet cells and EndoC-βH1 cells. Silencing of STAT1 or STAT2 individually did not prevent interferon-α-induced PDL1, while blocking of JAKs – a proposed therapeutic strategy for T1D – or IRF1 prevented PDL1 induction. Interpretation: These findings indicate that PDL1 is expressed in beta cells from people with T1D, possibly to attenuate the autoimmune assault, and that it is induced by both type I and II interferons via IRF1. Keywords: Type 1 diabetes, PDL1, PDL-1, Pancreatic beta cells, Pancreatic islets, IRF1, Immune checkpoint inhibitor, CD274