Aberrant thymic architecture and enhanced interferon signaling in Down syndrome

Individuals with Down syndrome (DS) have an elevated risk of autoimmune disease, particularly celiac disease, type 1 diabetes, and autoimmune hypothyroidism. In DS, thymi show characteristic structural and cellular changes, but the connection between these and the propensity to autoimmune disease is still unclear. Here we present a cell atlas from single cell RNA-sequencing (scRNA-seq) and spatial transcriptomics of age-matched thymi from infants with and without DS, which might contribute to filling this knowledge gap. DS does not significantly alter CD34+ diversity in the thymus; however, the gene expression changes we observe indicate altered differentiative potential in DS CD34+ cells. Although many genes involved in T-cell development and function (including USP16, RUNX1 and ETS2) are located on chromosome 21, several important T cell regulatory genes that are located on other chromosomes also change in DS. In contrast, CD34- DS thymocytes are characterised by maturation defects. CD34+ progenitors and proliferating DP thymocytes are in a functional state of chronic interferon activation. In summary, we identify several notable differences in key functional cellular subsets and pathways within the DS thymus, providing insights into the spatiotemporal dynamics of the thymic environment for this genetic condition. Down syndrome is a complex condition which results in immune alterations, including higher risk of autoimmune diseases. Here the authors show by single cell and spatial transcriptomics that the differentiation of thymic T cell precursors is disturbed in Down syndrome, which might underpin the functional alterations.