[HTML][HTML] PDL1 is expressed in the islets of people with type 1 diabetes and is up-regulated by interferons-α and-γ via IRF1 induction
EBioMedicine, 2018•thelancet.com
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 …
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 …
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.
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