Journal Article

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

Khor, Bernard, Tran, Khoa, Sharpe, Arlene H, Roche, Marly I, Bhan, Atul K, O'Shea, John J, Mordecai, Scott, Xavier, Ramnik J, Paterson, Alison M, Sundberg, Thomas B, Schirmer, Melanie, Schreiber, Stuart L, Shaw, Stanley Y, Gagnon, John D, Dombkowski, David, Tan, Pauline H, Medoff, Benjamin D, Shamji, Alykhan F, Conway, Kara L, Aldrich, Leslie N, Roychoudhuri, Rahul, Restifo, Nicholas P, Goel, Gautam

2015

Overview

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. Inflammation is used by the immune system to protect and repair tissues after an injury or infection. However, if inflammation is too strong, or goes on for too long, it can damage tissues. This is seen in autoimmune diseases such as inflammatory bowel disease and type 1 diabetes. Therefore, precise regulation of the inflammatory response is essential for maintaining human health. White blood cells known as T cells are central regulators of tissue inflammation. To achieve this goal, they develop into subtypes with specialized roles. For example, some T helper cells release chemical signals that trigger inflammation and other immune responses. Regulatory T (Treg) cells then shut down these immune responses once they are no longer needed. Many autoimmune and other inflammatory diseases are thought to arise—at least partially—because Treg cells fail to stop the inflammatory response. Boosting the number or the activity of Treg cells could therefore help to treat these diseases. However, technical difficulties have made it difficult to investigate the genes and molecular pathways that control how this subtype of white blood cells develops. Khor et al. thought that discovering new chemicals that increase the number of Treg cells without harming them could help to identify the pathways that control their development. Khor et al. screened over 3000 chemicals, many of which are drugs currently approved for use in humans, for their effect on immature T cells that were taken from mice and grown in the laboratory. This ‘unbiased chemical biology’ approach identified several chemicals that both encouraged the T cells to develop into Treg cells and reduced the numbers that became inflammation-promoting T helper cells. Khor et al. then focused on one of these chemicals, called harmine. Tests in mice showed that harmine reduces the extent of experimentally induced inflammatory reactions. Treg cells generated by treating immature T cells with harmine had the same effect. Further experiments showed that harmine exerts these effects, at least in part, by inhibiting the activity of a protein called DYRK1A. When DYRK1A was removed from maturing mouse T cells grown in the laboratory, the T cells tended to develop into anti-inflammatory Treg cells. These findings therefore identify DYRK1A as part of a pathway that suppresses the development of Treg cells. It remains to be discovered how it does this, and whether other DYRK protein family members have similar roles.

• Publisher: eLife Sciences Publications Ltd,eLife Sciences Publications, Ltd
• Subject: Animals / Autoimmunity / Autophagy / Biology / Cancer / Cell Culture Techniques / Cell Differentiation - immunology / Computational and Systems Biology / Cytokines / dual-specificity tyrosine-regulated kinase signaling / Dyrk Kinases / Gene expression / Harmine - pharmacology / Helper cells / Homeostasis / Homeostasis - immunology / Hospitals / Immunology / Immunoregulation / Inflammation / Inflammatory bowel disease / Inflammatory diseases / Kinases / Lymphatic system / Lymphocytes / Lymphocytes T / Medical research / Medical schools / Mice / Mice, Inbred C57BL / Mice, Knockout / Mucosa / Pathology / Phosphorylation / Protein Serine-Threonine Kinases - antagonists & inhibitors / Protein Serine-Threonine Kinases - genetics / Protein Serine-Threonine Kinases - metabolism / Protein-Tyrosine Kinases - antagonists & inhibitors / Protein-Tyrosine Kinases - genetics / Protein-Tyrosine Kinases - metabolism / Signal transduction / T cell differentiation / T cell receptors / T-Lymphocytes, Regulatory - metabolism / Th17 Cells - metabolism / Transcription factors / Tyrosine