The kinase DYRK1A reciprocally regulates the differentiation of Th17 and regulatory T cells
Bernard Khor,
John D Gagnon,
Gautam Goel,
Marly I Roche,
Kara L Conway,
Khoa Tran,
Leslie N Aldrich,
Thomas B Sundberg,
Alison M Paterson,
Scott Mordecai,
David Dombkowski,
Melanie Schirmer,
Pauline H Tan,
Atul K Bhan,
Rahul Roychoudhuri,
Nicholas P Restifo,
John J O'Shea,
Benjamin D Medoff,
Alykhan F Shamji,
Stuart L Schreiber,
Arlene H Sharpe,
Stanley Y Shaw,
Ramnik J Xavier
Affiliations
Bernard Khor
Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital, Harvard Medical School, Boston, United States; Center for Computational and Integrative Biology, Massachusetts General Hospital, Harvard Medical School, Boston, United States; Broad Institute of MIT and Harvard, Cambridge, United States; Pathology Service, Massachusetts General Hospital, Boston, United States
John D Gagnon
Broad Institute of MIT and Harvard, Cambridge, United States
Gautam Goel
Center for Computational and Integrative Biology, Massachusetts General Hospital, Harvard Medical School, Boston, United States
Marly I Roche
Pulmonary and Critical Care Unit, Massachusetts General Hospital, Boston, United States
Kara L Conway
Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital, Harvard Medical School, Boston, United States; Center for Computational and Integrative Biology, Massachusetts General Hospital, Harvard Medical School, Boston, United States; Broad Institute of MIT and Harvard, Cambridge, United States
Khoa Tran
Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, United States
Leslie N Aldrich
Broad Institute of MIT and Harvard, Cambridge, United States; Department of Chemistry and Chemical Biology, Harvard University, Cambridge, United States
Thomas B Sundberg
Broad Institute of MIT and Harvard, Cambridge, United States
Alison M Paterson
Department of Microbiology and Immunobiology, Harvard Medical School, Boston, United States; Department of Pathology, Brigham & Women's Hospital, Harvard Medical School, Boston, United States
Scott Mordecai
Pathology Service, Massachusetts General Hospital, Boston, United States
David Dombkowski
Pathology Service, Massachusetts General Hospital, Boston, United States
Melanie Schirmer
Broad Institute of MIT and Harvard, Cambridge, United States
Pauline H Tan
Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, United States
Atul K Bhan
Pathology Service, Massachusetts General Hospital, Boston, United States
Rahul Roychoudhuri
Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, United States
Nicholas P Restifo
Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, United States
John J O'Shea
Molecular Immunology and Inflammation Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, United States
Benjamin D Medoff
Pulmonary and Critical Care Unit, Massachusetts General Hospital, Boston, United States
Alykhan F Shamji
Broad Institute of MIT and Harvard, Cambridge, United States
Stuart L Schreiber
Broad Institute of MIT and Harvard, Cambridge, United States; Department of Chemistry and Chemical Biology, Harvard University, Cambridge, United States
Arlene H Sharpe
Department of Microbiology and Immunobiology, Harvard Medical School, Boston, United States; Department of Pathology, Brigham & Women's Hospital, Harvard Medical School, Boston, United States
Stanley Y Shaw
Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, United States
Ramnik J Xavier
Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital, Harvard Medical School, Boston, United States; Center for Computational and Integrative Biology, Massachusetts General Hospital, Harvard Medical School, Boston, United States; Broad Institute of MIT and Harvard, Cambridge, United States
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.
