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

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 k...

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Main Authors:	Khor, Bernard, Gagnon, John D, Goel, Gautam, Roche, Marly I, Conway, Kara L, Tran, Khoa, Aldrich, Leslie N, Sundberg, Thomas B, Paterson, Alison M, Mordecai, Scott, Dombkowski, David, Schirmer, Melanie, Tan, Pauline H, Bhan, Atul K, Roychoudhuri, Rahul, Restifo, Nicholas P, O'Shea, John J, Medoff, Benjamin D, Shamji, Alykhan F, Schreiber, Stuart L, Sharpe, Arlene H, Shaw, Stanley Y, Xavier, Ramnik J
Format:	Online
Language:	English
Published:	eLife Sciences Publications, Ltd 2015
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4441007/

id	pubmed-4441007
recordtype	oai_dc
spelling	pubmed-44410072015-05-26 The kinase DYRK1A reciprocally regulates the differentiation of Th17 and regulatory T cells Khor, Bernard Gagnon, John D Goel, Gautam Roche, Marly I Conway, Kara L Tran, Khoa Aldrich, Leslie N Sundberg, Thomas B Paterson, Alison M Mordecai, Scott Dombkowski, David Schirmer, Melanie Tan, Pauline H Bhan, Atul K Roychoudhuri, Rahul Restifo, Nicholas P O'Shea, John J Medoff, Benjamin D Shamji, Alykhan F Schreiber, Stuart L Sharpe, Arlene H Shaw, Stanley Y Xavier, Ramnik J Computational and Systems Biology 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. eLife Sciences Publications, Ltd 2015-05-22 /pmc/articles/PMC4441007/ /pubmed/25998054 http://dx.doi.org/10.7554/eLife.05920 Text en http://creativecommons.org/publicdomain/zero/1.0/ This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication (http://creativecommons.org/publicdomain/zero/1.0/) .
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Khor, Bernard Gagnon, John D Goel, Gautam Roche, Marly I Conway, Kara L Tran, Khoa Aldrich, Leslie N Sundberg, Thomas B Paterson, Alison M Mordecai, Scott Dombkowski, David Schirmer, Melanie Tan, Pauline H Bhan, Atul K Roychoudhuri, Rahul Restifo, Nicholas P O'Shea, John J Medoff, Benjamin D Shamji, Alykhan F Schreiber, Stuart L Sharpe, Arlene H Shaw, Stanley Y Xavier, Ramnik J
spellingShingle	Khor, Bernard Gagnon, John D Goel, Gautam Roche, Marly I Conway, Kara L Tran, Khoa Aldrich, Leslie N Sundberg, Thomas B Paterson, Alison M Mordecai, Scott Dombkowski, David Schirmer, Melanie Tan, Pauline H Bhan, Atul K Roychoudhuri, Rahul Restifo, Nicholas P O'Shea, John J Medoff, Benjamin D Shamji, Alykhan F Schreiber, Stuart L Sharpe, Arlene H Shaw, Stanley Y Xavier, Ramnik J The kinase DYRK1A reciprocally regulates the differentiation of Th17 and regulatory T cells
author_facet	Khor, Bernard Gagnon, John D Goel, Gautam Roche, Marly I Conway, Kara L Tran, Khoa Aldrich, Leslie N Sundberg, Thomas B Paterson, Alison M Mordecai, Scott Dombkowski, David Schirmer, Melanie Tan, Pauline H Bhan, Atul K Roychoudhuri, Rahul Restifo, Nicholas P O'Shea, John J Medoff, Benjamin D Shamji, Alykhan F Schreiber, Stuart L Sharpe, Arlene H Shaw, Stanley Y Xavier, Ramnik J
author_sort	Khor, Bernard
title	The kinase DYRK1A reciprocally regulates the differentiation of Th17 and regulatory T cells
title_short	The kinase DYRK1A reciprocally regulates the differentiation of Th17 and regulatory T cells
title_full	The kinase DYRK1A reciprocally regulates the differentiation of Th17 and regulatory T cells
title_fullStr	The kinase DYRK1A reciprocally regulates the differentiation of Th17 and regulatory T cells
title_full_unstemmed	The kinase DYRK1A reciprocally regulates the differentiation of Th17 and regulatory T cells
title_sort	kinase dyrk1a reciprocally regulates the differentiation of th17 and regulatory t cells
description	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.
publisher	eLife Sciences Publications, Ltd
publishDate	2015
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4441007/
_version_	1613226839330783232

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

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