The kinase DYRK1A reciprocally regulates the differentiation of Th17 and regulatory T cells

The balance between Th17 and T regulatory (T(reg)) cells critically modulates immune homeostasis, with an inadequate T(reg) response contributing to inflammatory disease. Using an unbiased chemical biology approach, we identified a novel role for the dual specificity tyrosine-phosphorylation-regulated kinase DYRK1A in regulating this balance. Inhibition of DYRK1A enhances T(reg) differentiation and impairs Th17 differentiation without affecting known pathways of T(reg)/Th17 differentiation. Thus, DYRK1A represents a novel mechanistic node at the branch point between commitment to either T(reg) or Th17 lineages. Importantly, both T(reg) cells generated using the DYRK1A inhibitor harmine and direct administration of harmine itself potently attenuate inflammation in multiple experimental models of systemic autoimmunity and mucosal inflammation. Our results identify DYRK1A as a physiologically relevant regulator of T(reg) cell differentiation and suggest a broader role for other DYRK family members in immune homeostasis. These results are discussed in the context of human diseases associated with dysregulated DYRK activity. DOI: http://dx.doi.org/10.7554/eLife.05920.001