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

ARAYA, PAULA; WAUGH, KATHERINE A.; SULLIVAN, KELLY D.; NÚÑEZ, NICOLÁS G.; ROSELLI, EMILIANO; SMITH, KEITH P.; GRANRATH, ROSS E.; RACHUBINSKI, ANGELA L.; ENRIQUEZ ESTRADA, BELINDA; BUTCHER, ERIC T.; MINTER, ROSS; TUTTLE, KATHRYN D.; BRUNO, TULLIA C.; MACCIONI, MARIANA; ESPINOSA, JOAQUÍN M.

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA

NATL ACAD SCIENCES

Lugar: Washington DC, USA; Año: 2019

0027-8424

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 frompeople 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 withand without autoimmune conditions. CD8+ T cells from adultswith DS are depleted of naïve subsets and enriched for differentiated subsets, express higher levels of markers of activation andsenescence (e.g., IFN-γ, Granzyme B, PD-1, KLRG1), and overproduce cytokines tied to autoimmunity (e.g., TNF-α). ConventionalCD4+ T cells display increased differentiation, polarization towardthe Th1 and Th1/17 states, and overproduction of the autoimmunityrelated cytokines IL-17A and IL-22. Plasma cytokine analysis confirmselevation of multiple autoimmunity-related cytokines (e.g., TNF-α,IL17A?D, IL-22) in people with DS, independent of diagnosis ofautoimmunity. Although Tregs are more abundant in DS, functionalassays 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 strongsignatures of T cell differentiation and activation that correlate positively with IFN hyperactivity. Finally, mass cytometry analysis of 8IFN-inducible phosphoepitopes demonstrates that T cell subsets withT21 show elevated levels of basal IFN signaling and hypersensitivityto IFN-α stimulation. Therefore, these results point to T cell dysregulation associated with IFN hyperactivity as a contributor to autoimmunity in DS