期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 116, 期 48, 页码 24231-24241出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1908129116
关键词
trisomy 21; T cells; autoimmunity; type I interferon; inflammation
资金
- NIH [R01AI150305, R01AI145988, R01AI141662, T32CA190216, UL1TR002535, P30CA046934]
- NSF [MCB1817582]
- Linda Crnic Institute for Down Syndrome
- Global Down Syndrome Foundation
- Anna and John J. Sie Foundation
- Human Immunology and Immunotherapy Initiative
- GI & Liver Innate Immune Program
- Proyectos de Investigacion Cientifica y Tecnologica Subsidio [2016-2414]
- Secretaria de Ciencia y Tecnologia de la Universidad Nacional de Cordoba
- CONICET
- Boettcher Foundation
- University Research Priority Program
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 naive subsets and enriched for differentiated subsets, express higher levels of markers of activation and senescence (e.g., IFN-gamma, Granzyme B, PD-1, KLRG1), and overproduce cytokines tied to autoimmunity (e.g., TNF-alpha). 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-alpha, IL17A-D, 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-alpha stimulation. Therefore, these results point to T cell dysregulation associated with IFN hyperactivity as a contributor to autoimmunity in DS.
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