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However, the mechanisms by which T21 dysregulates adaptive immunity across the lifespan remain poorly understood. We report here a multimodal analysis of adaptive immunity across development and aging in DS, including deep B cell profiling by mass cytometry matched to transcriptome and proteome data, B and T cell receptor sequencing (BCR, TCR), and spatial transcriptomics of tonsil tissue. T21 causes progressive shifts in B cell subsets together with accelerated age-dependent B cell loss linked to hyperactive interferon and JAK\/STAT signaling. The peripheral immunoglobulin repertoire shows dysregulated class switching, progressive loss of diversity, differential VDJ usage, and imbalanced rates of somatic hypermutation across immunoglobulin isotypes mirrored by contraction and skewing of the TCR repertoire. In children with DS, tonsil tissues are highly disorganized with smaller germinal centers, fibrotic intrusions, lower rates of cell proliferation, strong inflammatory signaling, and transcriptional programs indicative of dysregulated lymphocyte homing and residence. Together, these results point to hyperactive interferon signaling as a driver of dysregulated adaptive immunity in DS amenable to early therapeutic intervention.<\/jats:p>","DOI":"10.64898\/2026.07.30.741516","type":"posted-content","created":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T02:05:24Z","timestamp":1785895524000},"source":"Crossref","is-referenced-by-count":0,"title":["Progressive deterioration of adaptive immune repertoires in Down syndrome linked to interferon hyperactivity and lymphoid tissue disorganization"],"prefix":"10.64898","author":[{"given":"Micah G.","family":"Donovan","sequence":"first","affiliation":[{"name":"Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz; Aurora, USA"},{"name":"Department of Pharmacology, University of Colorado Anschutz; Aurora, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neetha Paul","family":"Eduthan","sequence":"additional","affiliation":[{"name":"Linda Crnic Institute for Down 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