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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2019,11,26]]},"abstract":"<jats:p>Trisomy 21 (T21) causes Down syndrome (DS), a condition characterized by high prevalence of autoimmune disorders. However, the molecular and cellular mechanisms driving this phenotype remain unclear. Building upon our previous finding that T cells from people with DS show increased expression of interferon (IFN)-stimulated genes, we have completed a comprehensive characterization of the peripheral T cell compartment in adults with DS with and without autoimmune conditions. CD8+ T cells from adults with DS are depleted of na\u00efve subsets and enriched for differentiated subsets, express higher levels of markers of activation and senescence (e.g., IFN-\u03b3, Granzyme B, PD-1, KLRG1), and overproduce cytokines tied to autoimmunity (e.g., TNF-\u03b1). Conventional CD4+ T cells display increased differentiation, polarization toward the Th1 and Th1\/17 states, and overproduction of the autoimmunity-related cytokines IL-17A and IL-22. Plasma cytokine analysis confirms elevation of multiple autoimmunity-related cytokines (e.g., TNF-\u03b1, IL17A\u2013D, IL-22) in people with DS, independent of diagnosis of autoimmunity. Although Tregs are more abundant in DS, functional assays show that CD8+ and CD4+ effector T cells with T21 are resistant to Treg-mediated suppression, regardless of Treg karyotype. Transcriptome analysis of white blood cells and T cells reveals strong signatures of T cell differentiation and activation that correlate positively with IFN hyperactivity. Finally, mass cytometry analysis of 8 IFN-inducible phosphoepitopes demonstrates that T cell subsets with T21 show elevated levels of basal IFN signaling and hypersensitivity to IFN-\u03b1 stimulation. Therefore, these results point to T cell dysregulation associated with IFN hyperactivity as a contributor to autoimmunity in DS.<\/jats:p>","DOI":"10.1073\/pnas.1908129116","type":"journal-article","created":{"date-parts":[[2019,11,7]],"date-time":"2019-11-07T19:35:19Z","timestamp":1573155319000},"page":"24231-24241","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":156,"title":["Trisomy 21 dysregulates T cell lineages toward an autoimmunity-prone state associated with interferon hyperactivity"],"prefix":"10.1073","volume":"116","author":[{"given":"Paula","family":"Araya","sequence":"first","affiliation":[{"name":"Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, CO 80045;"},{"name":"Departamento de Bioqu\u00edmica Cl\u00ednica, Centro de Investigaciones en Bioqu\u00edmica Cl\u00ednica e Inmunolog\u00eda (CIBICI), Consejo Nacional de Investigaciones Cient\u00edficas y T\u00e9cnicas 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