Impaired IL-27 Mediated Control of CD4+ T Cell Function Impacts on Ectopic Lymphoid Structure Formation in Patients with Sjögren's Syndrome

OBJECTIVES: Ectopic lymphoid structures (ELS) develop at sites of infection, autoimmunity and cancer. In patients with Sjogren's syndrome (SS), ELS support autoreactive B-cell activation and support lymphomagenesis. IL-27 is a key regulator of adaptive immunity and limits Th17 cell-driven pathology. Here, we elucidated the role of IL-27 in ELS formation and function in autoimmunity using a murine model of sialadenitis and in patients with SS.

METHODS: ELS formation was induced in wild-type and IL27ra-/- mice via salivary gland (SG) cannulation of a replication-deficient adenovirus in the presence/absence of IL-17A neutralization. In SG biopsies IL-27-producing cells were identified by multicolour immune-fluorescence microscopy. Lesional and circulating IL-27 levels were determined by gene expression and ELISA. The in-vitro effect of IL-27 on T-cells was determined by FACS and cytokine release.

RESULTS: In experimental sialadenitis, Il27ra-/- mice had larger and hyperactive ELS (focus score P<0.001), increased autoimmunity and an expanded Th17 response (P<0.001) compared to wild-type. IL-17 blockade in Il27ra-/- mice suppressed the aberrant ELS response (B and T cell reduction against control P<0.01). SS patients displayed increased circulating IL-27 (P<0.01) and in SG biopsies IL-27 was expressed by DC-LAMP+ dendritic cells in association with CD3+ T-cells. Remarkably, in SS T-cells but not in T-cells from patients with rheumatoid arthritis or healthy controls, IL-27-mediated suppression of IL-17 secretion was severely impaired and associated with an aberrant IFN-γ release upon IL-27 stimulation.

CONCLUSIONS: Our data indicate that the physiological ability of IL-27 to limit the magnitude and function of ELS through control of Th17 cell expansion is severely impaired in SS patients highlighting a defective immunoregulatory checkpoint in this condition.