Altered follicular immunity in secondary lymphoid organs is associated with interferon hyperactivity in Down syndrome

Down syndrome, caused by trisomy 21, is characterized by chronic interferon associated inflammation and immune dysregulation, yet the contribution of human secondary lymphoid organs to shaping this immune landscape remains unclear. Using multimodal single-cell and spatial profiling of human tonsils, we identify extensive remodeling of immune organization in trisomy 21. CD4 T cells are skewed away from canonical follicular helper (TFH) programs toward inflammatory TFH1 like and cytotoxic helper states enriched for interferon-responsive transcriptional programs. Tonsillar TFH cells exhibit increased interferon gamma and interleukin 21 production, indicating inflammatory skewing toward type 1 helper immunity. These alterations are accompanied by changes in dendritic cell and CD8 T cell compartments, reduced follicular size, increased extrafollicular TFH1/ B-cell proximity and altered B cell differentiation trajectories. Together, our findings identify trisomy 21 as a unique human context to investigate how chronic interferon-associated inflammation reshapes lymphoid tissue organization and adaptive immune cell fate decisions.