Endogenous programmed death ligand-1 restrains the development and onset of Sjӧgren's syndrome in non-obese diabetic mice.

Jing Zhou,Qing Yu,Toshihisa Kawai,Jun-O Jin

doi:10.1038/srep39105

Abstract

Programmed death-ligand 1 (PD-L1) down-modulates various immune responses by engaging the co-inhibitory receptor programmed death-1. Expression of PD-L1 and programmed death-1 is elevated in the salivary glands of patients with Sjögren’s syndrome (SS). The objective of this study is to define the role of endogenous PD-L1 in SS pathogenesis in non-obese diabetic (NOD) mouse model of this disease. We inhibited endogenous PD-L1 function by intraperitoneal administration of a blocking antibody to 6 week-old female NOD/ShiLtJ mice repeatedly during a 9-day period. PD-L1 blockade accelerated leukocyte infiltration and caspase-3 activation in the submandibular gland (SMG), production of antinuclear and anti-M3 muscarinic acetylcholine receptor (M3R) autoantibodies and impairment of saliva secretion, indicative of accelerated development and onset of SS. The effect of PD-L1 blockade was associated with increased T- and B cells and T helper 1 cytokine IFN-γ in the SMG. Local administration of exogenous IFN-γ to the SMG led to impaired salivary secretion accompanied by down-regulation of aquaporin 5 and an increase in anti-M3R autoantibodies. Conversely, neutralization of IFN-γ markedly improved salivary secretion and aquaporin 5 expression in anti-PD-L1-treated NOD/ShiLtJ mice. Hence, endogenous PD-L1 hinders the development and onset of SS in NOD mice, in part by suppressing IFN-γ production.

Highlights

Approaches that can attenuate Th1/Tc1 responses and IFN-γproduction may have preventive or therapeutic potentials for s syndrome (SS) disease
To examine whether programmed death-ligand 1 (PD-L1) and PD-1 expression is elevated during the development of SS-like disease in non-obese diabetic (NOD)/ShiLtJ mice, we determined their mRNA levels in the submandibular glands (SMG) from these mice at various ages
The results showed that the disease onset started around 10 weeks of age in the great majority of these mice, based on the presence of leukocyte foci in the SMG and antinuclear antibodies (ANA) in the serum, as well as an impaired stimulated salivary flow rate compared to mice aged 4 weeks and control Balb/c mice

Summary

Introduction

Approaches that can attenuate Th1/Tc1 responses and IFN-γproduction may have preventive or therapeutic potentials for SS disease. Loss-of-function studies in mouse models demonstrate that the endogenous PD-L1-PD1 activities restrain the development and reduce the severity of lupus-like glomerulonephritis and arthritis, EAE, autoimmune diabetes and collagen-induced arthritis[29,42,43]. PD-L1 and PD-1 expression are elevated in salivary gland epithelial cells and salivary gland-infiltrating lymphocytes, respectively, in SS patients[35], suggesting a potential immune-suppressive and disease-inhibiting role of PD-L1-PD-1 pathway in this disease. We investigated the role of endogenous PD-L1 in SS by inhibiting its function in non-obese diabetic (NOD) mice, a widely used model of SS, and demonstrated an inhibitory effect of endogenous PD-L1 that hinders the development and onset of this disease

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