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In patients with Sj\u00f6gren's syndrome (SS<\/jats:styled-content>), ELS<\/jats:styled-content> support autoreactive B cell activation and lymphomagenesis. Interleukin\u201027 (IL<\/jats:styled-content>\u201027) is a key regulator of adaptive immunity and limits Th17 cell\u2013driven pathology. We undertook this study to elucidate the role of IL<\/jats:styled-content>\u201027 in ELS<\/jats:styled-content> formation and function in autoimmunity using a murine model of sialadenitis and in patients with SS<\/jats:styled-content>.<\/jats:p><\/jats:sec>Methods<\/jats:title>ELS<\/jats:styled-content> formation was induced in wild\u2010type and Il27ra<\/jats:italic>\u2212<\/jats:italic>\/\u2212<\/jats:italic><\/jats:sup> mice via salivary gland (SG<\/jats:styled-content>) cannulation of a replication\u2010deficient adenovirus in the presence or absence of IL<\/jats:styled-content>\u201017A neutralization. In SG<\/jats:styled-content> biopsy samples, IL<\/jats:styled-content>\u201027\u2013producing cells were identified by multicolor immunofluorescence microscopy. Lesional and circulating IL<\/jats:styled-content>\u201027 levels were determined by gene expression and enzyme\u2010linked immunosorbent assay. The in vitro effect of IL<\/jats:styled-content>\u201027 on T cells was assessed using fluorescence\u2010activated cell sorting and cytokine release.<\/jats:p><\/jats:sec>Results<\/jats:title>In experimental sialadenitis, Il27ra<\/jats:italic>\u2212\/\u2212<\/jats:sup> mice had larger and more hyperactive ELS<\/jats:styled-content> (focus score; P<\/jats:italic> < 0.001), increased autoimmunity, and an expanded Th17 response (P<\/jats:italic> < 0.001), compared to wild\u2010type mice. IL<\/jats:styled-content>\u201017 blockade in Il27ra<\/jats:italic>\u2212<\/jats:italic>\/\u2212<\/jats:italic><\/jats:sup> mice suppressed the aberrant ELS<\/jats:styled-content> response (B and T cell reduction against control; P<\/jats:italic> < 0.01). SS<\/jats:styled-content> patients displayed increased circulating IL<\/jats:styled-content>\u201027 levels (P<\/jats:italic> < 0.01), and in SG<\/jats:styled-content> biopsy samples, IL<\/jats:styled-content>\u201027 was expressed by DC<\/jats:styled-content>\u2010LAMP<\/jats:styled-content>+ dendritic cells in association with CD<\/jats:styled-content>3+ T cells. Remarkably, in SS<\/jats:styled-content> T cells (but not in T cells from patients with rheumatoid arthritis or healthy controls), IL<\/jats:styled-content>\u201027\u2013mediated suppression of IL<\/jats:styled-content>\u201017 secretion was severely impaired and associated with an aberrant interferon\u2010\u03b3 release upon IL<\/jats:styled-content>\u201027 stimulation.<\/jats:p><\/jats:sec>Conclusion<\/jats:title>Our data indicate that the physiologic ability of IL<\/jats:styled-content>\u201027 to limit the magnitude and function of ELS<\/jats:styled-content> through control of Th17 cell expansion is severely impaired in SS<\/jats:styled-content> patients, highlighting a defective immunoregulatory checkpoint in this condition.<\/jats:p><\/jats:sec>","DOI":"10.1002\/art.41289","type":"journal-article","created":{"date-parts":[[2020,4,20]],"date-time":"2020-04-20T03:48:56Z","timestamp":1587354536000},"page":"1559-1570","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["Impaired Interleukin\u201027\u2013Mediated Control of CD<\/scp>4+ T Cell Function Impact on Ectopic Lymphoid Structure Formation in Patients With Sj\u00f6gren's Syndrome"],"prefix":"10.1002","volume":"72","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8019-556X","authenticated-orcid":false,"given":"Davide","family":"Lucchesi","sequence":"first","affiliation":[{"name":"Queen Mary University of London London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2490-0199","authenticated-orcid":false,"given":"Rachel","family":"Coleby","sequence":"additional","affiliation":[{"name":"Queen Mary University of London London 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