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The kinase DYRK1A reciprocally regulates the differentiation of Th17 and regulatory T cells
The balance between Th17 and T regulatory (T(reg)) cells critically modulates immune homeostasis, with an inadequate T(reg) response contributing to inflammatory disease. Using an unbiased chemical biology approach, we identified a novel role for the dual specificity tyrosine-phosphorylation-regulat...
| Autores principales: | , , , , , , , , , , , , , , , , , , , , , , |
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| Formato: | Online Artículo Texto |
| Lenguaje: | English |
| Publicado: |
eLife Sciences Publications, Ltd
2015
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| Materias: | |
| Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4441007/ https://www.ncbi.nlm.nih.gov/pubmed/25998054 http://dx.doi.org/10.7554/eLife.05920 |
| _version_ | 1782372726857531392 |
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| 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 |
| 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 |
| collection | PubMed |
| description | The balance between Th17 and T regulatory (T(reg)) cells critically modulates immune homeostasis, with an inadequate T(reg) 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 T(reg) differentiation and impairs Th17 differentiation without affecting known pathways of T(reg)/Th17 differentiation. Thus, DYRK1A represents a novel mechanistic node at the branch point between commitment to either T(reg) or Th17 lineages. Importantly, both T(reg) 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 T(reg) 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. DOI: http://dx.doi.org/10.7554/eLife.05920.001 |
| format | Online Article Text |
| id | pubmed-4441007 |
| institution | National Center for Biotechnology Information |
| language | English |
| publishDate | 2015 |
| publisher | eLife Sciences Publications, Ltd |
| record_format | MEDLINE/PubMed |
| 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 eLife Computational and Systems Biology The balance between Th17 and T regulatory (T(reg)) cells critically modulates immune homeostasis, with an inadequate T(reg) 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 T(reg) differentiation and impairs Th17 differentiation without affecting known pathways of T(reg)/Th17 differentiation. Thus, DYRK1A represents a novel mechanistic node at the branch point between commitment to either T(reg) or Th17 lineages. Importantly, both T(reg) 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 T(reg) 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. DOI: http://dx.doi.org/10.7554/eLife.05920.001 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/) . |
| spellingShingle | Computational and Systems Biology 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 |
| title | 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_short | 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 |
| topic | Computational and Systems Biology |
| url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4441007/ https://www.ncbi.nlm.nih.gov/pubmed/25998054 http://dx.doi.org/10.7554/eLife.05920 |
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