Mass-cytometry reveals global immune remodeling with multi-lineage hypersensitivity to Type I Interferon in Down syndrome

Abstract

Abstract People with Down syndrome (DS), the genetic condition caused by trisomy of chromosome 21 (chr21), have an altered disease spectrum. For example, adults with DS are largely protected from solid tumors while predisposed to various autoimmune disorders, early-onset Alzheimer’s disease, and severe respiratory infection. While the immune system is known to play a key role in these comorbidities among the disomic population, there is a dearth of immune studies in adults with DS. Here, we applied the single-cell, systems-level approach of mass-cytometry, or Cytometry by Time-Of-Flight (CyTOF), to broadly define phenotypic and functional alterations in immune homeostasis in adults with DS that are relevant to the potentiation of comorbidities associated with T21. We developed an innovative strategy to analyze CyTOF data, by incorporating techniques commonly used in genomics and even topography to eliminate batch bias and efficiently resolve ~100 immune cell types. This approach revealed that adults with DS have global immune dysregulation reminiscent of various inflammatory and autoimmune states enriched among older individuals of the disomic population. Upon stimulation directly ex vivo with Type I Interferon (IFN) and simultaneous detection of diverse phosphorylation events across the lymphoid and myeloid lineages, all immune subsets from individuals with T21 were hyper-responsive, but the degree of response and signaling pathways used varied among specific cell types. Notably, 4 of the 6 IFN receptor subunits for Types I, II, and III IFNs are encoded on chr21. Altogether, these results establish a critical foundation to pursue immune dysregulation and IFN hyperactivity as a driver of the altered disease spectrum in adults with DS.