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Cited by 179T-cell and B-cell ImmunologyDown syndrome and intellectual disability researchImmunodeficiency and Autoimmune Disorders

Trisomy 21 dysregulates T cell lineages toward an autoimmunity-prone state associated with interferon hyperactivity

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Araya, Paula, Waugh, Katherine A., Sullivan, Kelly D., Núñez, Nicolás G., Roselli, Emiliano, Smith, Keith P., Granrath, Ross E., Rachubinski, Angela L. +7 more·2019·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.1908129116PMC PMC6883781
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Abstract

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 naïve subsets and enriched for differentiated subsets, express higher levels of markers of activation and senescence (e.g., IFN-γ, Granzyme B, PD-1, KLRG1), and overproduce cytokines tied to autoimmunity (e.g., TNF-α). 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-α, 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-α stimulation. Therefore, these results point to T cell dysregulation associated with IFN hyperactivity as a contributor to autoimmunity in DS.

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  • Both individuals with DS and mouse models of DS experience constitutive hyperactivation of interferon (IFN) signaling with signs of chronic inflammation and immune dysregulation, which could exacerbate the neuroinflammatory response.

    “Notably, both individuals with DS and mouse models of DS experience constitutive hyperactivation of interferon (IFN) signaling with signs of chronic inflammation and immune dysregulation,30,31,32,33,34,35,36,37,38,39,40 that could exacerbate the neuroinflammatory response.”

    From Interferon signaling modulates Down syndrome-associated Alzheimer’s disease pathology in a mouse model (2025) · cites this paper as [34]

    The Abstract and Results report elevated basal IFN signaling, chronic inflammation, and T-cell dysregulation in people with Down syndrome. The paper does not establish the same findings in mouse models of Down syndrome, which are also included in the cited claim. The proposed neuroinflammatory consequence appears after the citations and is not treated as a finding attributed to this source. (LLM, conf=0.87)

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  • People with DS present increased IFN signaling likely driven by triplication of four of the six IFN receptors encoded on HSA21, rather than by massive elevation of IFN ligands, and this has been associated with chronic immune dysregulation.

    “people with DS present an increased IFN signaling likely driven by triplication of four of the six IFN receptors encoded on HSA21,36 rather than by massive elevation of the IFN ligands themselves as seen in interferonopathies,80 and this has been associated with chronic immune dysregulation.”

    From Interferon signaling modulates Down syndrome-associated Alzheimer’s disease pathology in a mouse model (2025) · cites this paper as [34]

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Authors
Araya, P., Waugh, K. A., Sullivan, K. D., Núñez, N. G., Roselli, E., Smith, K. P., Granrath, R. E., Rachubinski, A. L., Enriquez Estrada, B., Butcher, E. T., Minter, R., Tuttle, K. D., Bruno, T. C., Maccioni, M., & Espinosa, J. M.
Affiliations
  • Consejo Nacional de Investigaciones Científicas y Técnicas (AR)
  • University of Colorado Anschutz (US)
  • Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, CO 80045;
  • University of Pittsburgh (US)
Corresponding author
Maccioni, Mariana
ORCID
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
2019-11-07
Volume
116
Issue
48
Pages
24231-24241
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
DOI
10.1073/pnas.1908129116
PMC
PMC6883781
OpenAlex
W2988167777
Cited by
179
References
9
Citations by year
2026: 22 · 2025: 20 · 2024: 55 · 2023: 13 · 2022: 26 · 2021: 27 · 2020: 16
FWCI
6.89
Type
journal article
Language
en
Open access
Licence
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • Conicet (submittedVersion, cc-by-nc-sa)
Funders
  • Linda Crnic Institute for Down Syndrome (N/A)
  • Global Down Syndrome Foundation (N/A)
  • PICT-RAICES (2016-2414)
  • HHS | National Institutes of Health (T32CA190216, R01AI145988)
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
  • Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Down syndrome and intellectual disability research
  • Life Sciences › Immunology and Microbiology › Immunology › Immunodeficiency and Autoimmune Disorders
Keywords
Down syndrome, autoimmunity, T cell dysregulation, CD8+ T cells, CD4+ T cells, regulatory T cells, T cell differentiation, Th1/Th17 polarization, IL-17A, IL-22, TNF-α, T cell senescence, interferon signaling
MeSH terms
Adult, Cell Differentiation, Down Syndrome, Female, Humans, Interferon-gamma, Lymphocyte Activation, Male, Autoimmunity, Case-Control Studies, T-Lymphocyte Subsets, Interferon-alpha, Cellular Senescence, CD8-Positive T-Lymphocytes, Cell Lineage, Gene Expression Profiling, T-Lymphocytes, Regulatory, Young Adult

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