Malueg Matthew, Moo Keagan G, Arnett Azlann, Edwards Thomas H, Ruskin Susan L, Lambert Katharina, Subramanyam Aditi, Dufort Matthew J, Gersuk Vivian H, Partridge Rebecca, Buckner Jane H, Khor Bernard
Center for Translational Immunology, Benaroya Research Institute at Virginia Mason, Seattle, WA, United States.
Center for Systems Immunology, Benaroya Research Institute at Virginia Mason, Seattle, WA, United States.
Immunohorizons. 2025 Jan 23;9(1). doi: 10.1093/immhor/vlae005.
Dysregulated differentiation of naïve CD4+ T cells into T helper 17 (Th17) cells is likely a key factor predisposing to many autoimmune diseases. Therefore, better understanding how Th17 differentiation is regulated is essential to identify novel therapeutic targets and strategies to identify individuals at high risk of developing autoimmunity. Here, we extend our prior work using chemical inhibitors to provide mechanistic insight into a novel regulator of Th17 differentiation, the kinase dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A). We generated a conditional knockout mouse model to validate DYRK1A as a regulator of Th17 differentiation that acts in a dose-dependent fashion at least in part by modulating interleukin (IL)-6 signaling through multiple mechanisms. We identified a new role for DYRK1A in regulating surface expression of IL-6 receptor subunits in naïve CD4+ T cells, consistent with DYRK1A's impact on Th17 differentiation. Physiologic relevance is supported by findings in people with Down syndrome, in which increased expression of DYRK1A, encoded on chromosome 21, is linked to increased IL-6 responsiveness. Our findings highlight DYRK1A as a druggable target of broad therapeutic and prognostic interest in autoimmunity and immune function.
初始CD4+ T细胞向辅助性T细胞17（Th17）细胞的分化失调可能是导致许多自身免疫性疾病的关键因素。因此，更好地了解Th17分化是如何调控的，对于确定新的治疗靶点以及识别自身免疫性疾病高风险个体的策略至关重要。在此，我们扩展了之前使用化学抑制剂的研究工作，以深入了解Th17分化的一种新型调节因子——双特异性酪氨酸磷酸化调节激酶1A（DYRK1A）的作用机制。我们构建了一个条件性敲除小鼠模型，以验证DYRK1A作为Th17分化的调节因子，其至少部分通过多种机制调节白细胞介素（IL）-6信号传导，以剂量依赖的方式发挥作用。我们确定了DYRK1A在调节初始CD4+ T细胞中IL-6受体亚基表面表达方面的新作用，这与DYRK1A对Th17分化的影响一致。唐氏综合征患者的研究结果支持了其生理相关性，其中位于21号染色体上的DYRK1A表达增加与IL-6反应性增加有关。我们的研究结果突出了DYRK1A作为自身免疫和免疫功能中具有广泛治疗和预后意义的可药物化靶点。
