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This study was undertaken to measure the expression and function of the coinhibitory receptors (co\u2010IR<\/jats:styled-content>s) programmed cell death 1 (PD<\/jats:styled-content>\u20101), T cell immunoglobulin and ITIM<\/jats:styled-content> domain (TIGIT<\/jats:styled-content>), T cell immunoglobulin and mucin domain 3 (TIM<\/jats:styled-content>\u20103), and lymphocyte activation gene 3 (LAG<\/jats:styled-content>\u20103) in lymphocyte subsets from the peripheral blood of patients with SS<\/jats:styled-content>c.<\/jats:p><\/jats:sec>Methods<\/jats:title>Co\u2010IR<\/jats:styled-content> expression levels on subsets of immune cells were analyzed using a 16\u2010color flow cytometry panel. The functional role of co\u2010IR<\/jats:styled-content>s was determined by measuring cytokine production after in vitro stimulation of SS<\/jats:styled-content>c and healthy control peripheral blood mononuclear cells (PBMC<\/jats:styled-content>s) in the presence of co\u2010IR<\/jats:styled-content>\u2013blocking antibodies. Supernatants from cultures of stimulated PBMC<\/jats:styled-content>s were added to SS<\/jats:styled-content>c fibroblasts, and their impact on fibroblast gene expression was measured. Mathematical modeling was used to reveal differences between co\u2010IR<\/jats:styled-content> functions in SS<\/jats:styled-content>c patients and healthy controls.<\/jats:p><\/jats:sec>Results<\/jats:title>Levels of the co\u2010IR<\/jats:styled-content>s PD<\/jats:styled-content>\u20101 and TIGIT<\/jats:styled-content> were increased, and each was coexpressed, in distinct T cell subsets from SS<\/jats:styled-content>c patients compared to healthy controls. Levels of TIM<\/jats:styled-content>\u20103 were increased in SS<\/jats:styled-content>c natural killer cells. PD<\/jats:styled-content>\u20101, TIGIT<\/jats:styled-content>, and TIM<\/jats:styled-content>\u20103 antibody blockade revealed patient\u2010specific roles of each of these co\u2010IR<\/jats:styled-content>s in modulating activation\u2010induced T cell cytokine production. In contrast to healthy subjects, blockade of TIGIT<\/jats:styled-content> and TIM<\/jats:styled-content>\u20103, but not PD<\/jats:styled-content>\u20101, failed to reverse inhibited cytokine production in SS<\/jats:styled-content>c patients, indicating that enhanced T cell exhaustion is present in SS<\/jats:styled-content>c. Finally, cytokines secreted in anti\u2013TIM<\/jats:styled-content>\u20103\u2013treated PBMC<\/jats:styled-content> cultures distinctly changed the gene expression profile in SS<\/jats:styled-content>c fibroblasts.<\/jats:p><\/jats:sec>Conclusion<\/jats:title>The altered expression and regulatory capacity of co\u2010IR<\/jats:styled-content>s in SS<\/jats:styled-content>c lymphocytes may contribute to disease pathophysiology by modulating the cytokine\u2010mediated cross\u2010talk of immune cells and fibroblasts at sites of inflammation and\/or fibrosis.<\/jats:p><\/jats:sec>","DOI":"10.1002\/art.40399","type":"journal-article","created":{"date-parts":[[2017,12,16]],"date-time":"2017-12-16T16:49:57Z","timestamp":1513442997000},"page":"566-577","source":"Crossref","is-referenced-by-count":35,"title":["Increased Expression and Modulated Regulatory Activity of Coinhibitory Receptors PD<\/scp>\u20101, TIGIT<\/scp>, and TIM<\/scp>\u20103 in Lymphocytes From Patients With Systemic 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