Dissecting how DYRK1A-gp130 axis drives immune dysregulation in Down syndrome and beyond

About This Grant

PROJECT SUMMARY/ABSTRACT Autoimmunity is a major driver of chronic morbidity in over 15 million Americans, representing significant unmet medical need. Individuals with Down syndrome (DS, trisomy 21) are at especially increased risk (4-100x) of autoimmunity, suggesting a contributory role of genes on chromosome 21. We identified the chromosome 21- encoded kinase DYRK1A (studied almost exclusively in the context of neurodevelopment) as a candidate driver of autoimmunity risk. Better understanding the underlying mechanisms may highlight DYRK1A as a druggable target to treat or prevent autoimmunity in people with DS and subsets of people without DS. We showed that DYRK1 regulates differentiation of pro-autoimmunity Th17 cells. We further uncovered that this works at least in part by a novel regulatory role of DYRK1A on surface expression of the IL-6 receptor subunits gp130 and IL-6R. These findings highlight a much broader role for DYRK1A in autoimmune biology than previously appreciated because (i) IL-6 is a pleiotropic cytokine that drives autoimmunity through multiple mechanisms including but not limited to Th17 differentiation; and (ii) gp130 mediates signaling of many cytokines other than IL-6 including (immune-relevant) IL-11 and IL-27. Therefore, the DYRK1A-gp130 axis has broad potential to impact biology relevant to autoimmunity and beyond. We hypothesize that DYRK1A regulates cellular and functional response to IL-6 and other gp130 family cytokines in people and murine models of DS. We propose key experiments here to advance our understanding of the DYRK1A- gp130 axis (i) in people with and without DS, (ii) in cell types beyond naïve CD4+ T cells and (iii) in murine models of DS. Pilot high-risk high-reward approaches include first-in-kind immune studies of individuals with DYRK1A syndrome. Our specific aims are: Specific Aim 1. Define how DYRK1A regulates human gp130 signaling. These studies will define how the DYRK1A-gp130 axis is functionally altered and lay keystone data to rationally expand the scope of follow-up studies. Notably, we include people with DS and DYRK1A syndrome who naturally over-/under-express DYRK1A respectively. This first-in-kind allelic series allows unprecedented translationally relevant studies of DYRK1A in immunobiology, including novel studies in immune aging and autoimmune-poised state. Specific Aim 2. Validate altered DYRK1A/gp130 axis in murine models of DS. These studies test the hypothesis that the Dp16 model of DS shows similar dysregulation of the DYRK1A-gp130 axis as seen in people with DS. We further demonstrate unique utility of the murine model, including leveraging novel genetic models to demonstrate the causal role of DYRK1A and mechanistically dissecting T cell generation beyond Th17. This will generate first-in-kind data that the Dp16 model can and should be used to study DS- immunodysregulation.