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Elife. 2015 May 22;4. doi: 10.7554/eLife.05920.

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

Author information

1
Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital, Harvard Medical School, Boston, United States.
2
Broad Institute of MIT and Harvard, Cambridge, United States.
3
Center for Computational and Integrative Biology, Massachusetts General Hospital, Harvard Medical School, Boston, United States.
4
Pulmonary and Critical Care Unit, Massachusetts General Hospital, Boston, United States.
5
Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, United States.
6
Department of Microbiology and Immunobiology, Harvard Medical School, Boston, United States.
7
Pathology Service, Massachusetts General Hospital, Boston, United States.
8
Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, United States.
9
Molecular Immunology and Inflammation Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, United States.

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.

KEYWORDS:

T cell differentiation; computational biology; dual-specificity tyrosine-regulated kinase signaling; human; immunology; inflammation; mouse; systems biology

PMID:
25998054
PMCID:
PMC4441007
DOI:
10.7554/eLife.05920
[Indexed for MEDLINE]
Free PMC Article

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