Interferon-gamma drives programmed death-ligand 1 expression on islet ß cells to limit T cell function during autoimmune diabetes.
Sci Rep
; 8(1): 8295, 2018 05 29.
Article
in En
| MEDLINE
| ID: mdl-29844327
ABSTRACT
Type 1 diabetes is caused by autoreactive T cell-mediated ß cell destruction. Even though co-inhibitory receptor programmed death-1 (PD-1) restrains autoimmunity, the expression and regulation of its cognate ligands on ß cell remains unknown. Here, we interrogated ß cell-intrinsic programmed death ligand-1 (PD-L1) expression in mouse and human islets. We measured a significant increase in the level of PD-L1 surface expression and the frequency of PD-L1+ ß cells as non-obese diabetic (NOD) mice aged and developed diabetes. Increased ß cell PD-L1 expression was dependent on T cell infiltration, as ß cells from Rag1-deficient mice lacked PD-L1. Using Rag1-deficient NOD mouse islets, we determined that IFN-γ promotes ß cell PD-L1 expression. We performed analogous experiments using human samples, and found a significant increase in ß cell PD-L1 expression in type 1 diabetic samples compared to type 2 diabetic, autoantibody positive, and non-diabetic samples. Among type 1 diabetic samples, ß cell PD-L1 expression correlated with insulitis. In vitro experiments with human islets from non-diabetic individuals showed that IFN-γ promoted ß cell PD-L1 expression. These results suggest that insulin-producing ß cells respond to pancreatic inflammation and IFN-γ production by upregulating PD-L1 expression to limit self-reactive T cells.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
T-Lymphocytes
/
Islets of Langerhans
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Interferon-gamma
/
Diabetes Mellitus, Type 1
/
B7-H1 Antigen
Limits:
Animals
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Female
/
Humans
Language:
En
Journal:
Sci Rep
Year:
2018
Document type:
Article
Affiliation country:
Estados Unidos