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

Elife
Authors
Keywords
Abstract

The balance between Th17 and T regulatory (Treg) cells critically modulates immune homeostasis, with an inadequate Treg 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 Treg differentiation and impairs Th17 differentiation without affecting known pathways of Treg/Th17 differentiation. Thus, DYRK1A represents a novel mechanistic node at the branch point between commitment to either Treg or Th17 lineages. Importantly, both Treg 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 Treg 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.

Year of Publication
2015
Journal
Elife
Volume
4
Date Published
2015 May 22
ISSN
2050-084X
DOI
10.7554/eLife.05920
PubMed ID
25998054
PubMed Central ID
PMC4441007
Links
Grant list
T32 HL066987 / HL / NHLBI NIH HHS / United States
P30 DK043351 / DK / NIDDK NIH HHS / United States
T32 CA009216-31 / CA / NCI NIH HHS / United States
K08 DK104021-01 / DK / NIDDK NIH HHS / United States
T32 HL066987-12 / HL / NHLBI NIH HHS / United States
S10 OD012027-01A1 / OD / NIH HHS / United States
U01 DK062432 / DK / NIDDK NIH HHS / United States
105663/Z/14/Z / Wellcome Trust / United Kingdom
Intramural NIH HHS / United States
T32 CA009216 / CA / NCI NIH HHS / United States
K08 DK104021 / DK / NIDDK NIH HHS / United States
105663 / Wellcome Trust / United Kingdom
S10 OD012027 / OD / NIH HHS / United States