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

Dutto, J.; Bustos, J.; Boffelli, L.; Tosello-Boari, J.; Kienzler, J. C.; Araya, P.; Dhooge, S.; Guirado, A. F.; Biasi, P.; Baigorri, R. E.; Valeriani, C.; Richer, W.; Montes, C. d. C.; Cecconi, V.; Becher, B.; Espinosa, J. M.; Piaggio, E.; Nunez, N. G.; Maccioni, M.

doi:10.64898/2026.08.04.741562

bioRxiv · 10.64898/2026.08.04.741562

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

Dutto, J.·Bustos, J.·Boffelli, L.·Tosello-Boari, J.·Kienzler, J. C.·Araya, P.·Dhooge, S.·Guirado, A. F.·Biasi, P.·Baigorri, R. E.·Valeriani, C.·Richer, W.·Montes, C. d. C.·Cecconi, V.·Becher, B.·Espinosa, J. M.·Piaggio, E.·Nunez, N. G.·Maccioni, M.

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Abstract

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.

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Dutto, J., Bustos, J., Boffelli, L., Tosello-Boari, J., Kienzler, J. C., Araya, P., Dhooge, S., Guirado, A. F., Biasi, P., Baigorri, R. E., Valeriani, C., Richer, W., Montes, C. d. C., Cecconi, V., Becher, B., Espinosa, J. M., Piaggio, E., Nunez, N. G., Maccioni, M.. 2026-08-09. Altered follicular immunity in secondary lymphoid organs is associated with interferon hyperactivity in Down syndrome. https://doi.org/10.64898/2026.08.04.741562

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