title: The kinase DYRK1A reciprocally regulates the differentiation of Th17 and regulatory T cells.
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.
authors.affiliation: Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital, Harvard Medical School, Boston, United States.
authors.forename: Bernard
authors.initials: B
authors.lastname: Khor
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, United States.
authors.forename: John D
authors.initials: JD
authors.lastname: Gagnon
authors.affiliation: Center for Computational and Integrative Biology, Massachusetts General Hospital, Harvard Medical School, Boston, United States.
authors.forename: Gautam
authors.initials: G
authors.lastname: Goel
authors.affiliation: Pulmonary and Critical Care Unit, Massachusetts General Hospital, Boston, United States.
authors.forename: Marly I
authors.initials: MI
authors.lastname: Roche
authors.affiliation: Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital, Harvard Medical School, Boston, United States.
authors.forename: Kara L
authors.initials: KL
authors.lastname: Conway
authors.affiliation: Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, United States.
authors.forename: Khoa
authors.initials: K
authors.lastname: Tran
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, United States.
authors.forename: Leslie N
authors.initials: LN
authors.lastname: Aldrich
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, United States.
authors.forename: Thomas B
authors.initials: TB
authors.lastname: Sundberg
authors.affiliation: Department of Microbiology and Immunobiology, Harvard Medical School, Boston, United States.
authors.forename: Alison M
authors.initials: AM
authors.lastname: Paterson
authors.affiliation: Pathology Service, Massachusetts General Hospital, Boston, United States.
authors.forename: Scott
authors.initials: S
authors.lastname: Mordecai
authors.affiliation: Pathology Service, Massachusetts General Hospital, Boston, United States.
authors.forename: David
authors.initials: D
authors.lastname: Dombkowski
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, United States.
authors.forename: Melanie
authors.initials: M
authors.lastname: Schirmer
authors.affiliation: Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, United States.
authors.forename: Pauline H
authors.initials: PH
authors.lastname: Tan
authors.affiliation: Pathology Service, Massachusetts General Hospital, Boston, United States.
authors.forename: Atul K
authors.initials: AK
authors.lastname: Bhan
authors.affiliation: Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, United States.
authors.forename: Rahul
authors.initials: R
authors.lastname: Roychoudhuri
authors.affiliation: Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, United States.
authors.forename: Nicholas P
authors.initials: NP
authors.lastname: Restifo
authors.affiliation: Molecular Immunology and Inflammation Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, United States.
authors.forename: John J
authors.initials: JJ
authors.lastname: O'Shea
authors.affiliation: Pulmonary and Critical Care Unit, Massachusetts General Hospital, Boston, United States.
authors.forename: Benjamin D
authors.initials: BD
authors.lastname: Medoff
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, United States.
authors.forename: Alykhan F
authors.initials: AF
authors.lastname: Shamji
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, United States.
authors.forename: Stuart L
authors.initials: SL
authors.lastname: Schreiber
authors.affiliation: Department of Microbiology and Immunobiology, Harvard Medical School, Boston, United States.
authors.forename: Arlene H
authors.initials: AH
authors.lastname: Sharpe
authors.affiliation: Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, United States.
authors.forename: Stanley Y
authors.initials: SY
authors.lastname: Shaw
authors.affiliation: Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital, Harvard Medical School, Boston, United States.
authors.forename: Ramnik J
authors.initials: RJ
authors.lastname: Xavier
mesh_terms: D000818:Animals; D018929:Cell Culture Techniques; D002454:Cell Differentiation / Q000276:immunology*; D006247:Harmine / Q000494:pharmacology; D006706:Homeostasis / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D050378:T-Lymphocytes, Regulatory / Q000378:metabolism*; D058504:Th17 Cells / Q000378:metabolism*; D000097603:Dyrk Kinases
chemical_list: D006247:Harmine; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D000097603:Dyrk Kinases
keywords: T cell differentiation; computational biology; dual-specificity tyrosine-regulated kinase signaling; human; immunology; inflammation; mouse; systems biology