Impaired Interleukin-27-Mediated Control of CD4+ T Cell Function Impact on Ectopic Lymphoid Structure Formation in Patients With Sjögren's Syndrome.

Arthritis & rheumatology (Hoboken, N.J.) 2020 Sep

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Ectopic lymphoid structures (ELS) develop at sites of infection, autoimmunity, and cancer. In patients with Sjögren's syndrome (SS), ELS support autoreactive B cell activation and lymphomagenesis. Interleukin-27 (IL-27) is a key regulator of adaptive immunity and limits Th17 cell-driven pathology. We undertook this study to elucidate the role of IL-27 in ELS formation and function in autoimmunity using a murine model of sialadenitis and in patients with SS. ELS formation was induced in wild-type and Il27ra-/- mice via salivary gland (SG) cannulation of a replication-deficient adenovirus in the presence or absence of IL-17A neutralization. In SG biopsy samples, IL-27-producing cells were identified by multicolor immunofluorescence microscopy. Lesional and circulating IL-27 levels were determined by gene expression and enzyme-linked immunosorbent assay. The in vitro effect of IL-27 on T cells was assessed using fluorescence-activated cell sorting and cytokine release. In experimental sialadenitis, Il27ra-/- mice had larger and more hyperactive ELS (focus score; P < 0.001), increased autoimmunity, and an expanded Th17 response (P < 0.001), compared to wild-type mice. 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 levels (P < 0.01), and in SG biopsy samples, 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 interferon-γ release upon IL-27 stimulation. Our data indicate that the physiologic 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. © 2020 The Authors. Arthritis & Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.

Citation

Davide Lucchesi, Rachel Coleby, Elena Pontarini, Edoardo Prediletto, Felice Rivellese, David G Hill, Alicia Derrac Soria, Simon A Jones, Ian R Humphreys, Nurhan Sutcliffe, Anwar R Tappuni, Costantino Pitzalis, Gareth W Jones, Michele Bombardieri. Impaired Interleukin-27-Mediated Control of CD4+ T Cell Function Impact on Ectopic Lymphoid Structure Formation in Patients With Sjögren's Syndrome. Arthritis & rheumatology (Hoboken, N.J.). 2020 Sep;72(9):1559-1570