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

Khor B, Gagnon JD, Goel G, Roche MI, Conway KL, Tran K, Aldrich LN, Sundberg TB, Paterson AM, Mordecai S, Dombkowski D, Schirmer M, Tan PH, Bhan AK, Roychoudhuri R, Restifo NP, O'Shea JJ, Medoff BD, Shamji AF, Schreiber SL, Sharpe AH, Shaw SY, Xavier RJ - Elife (2015)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital, Harvard Medical School, Boston, United States.

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.

No MeSH data available.


Related in: MedlinePlus

Euclidean distance clustering analysis of gene expression data from cell lines treated with Treg enhancers first analyzed by principal component analysis.DOI:http://dx.doi.org/10.7554/eLife.05920.011
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fig1s8: Euclidean distance clustering analysis of gene expression data from cell lines treated with Treg enhancers first analyzed by principal component analysis.DOI:http://dx.doi.org/10.7554/eLife.05920.011

Mentions: The L1000 method had previously been used to generate gene expression data from three different cell lines treated with numerous compounds, including most of the Treg cell enhancers identified here (expression data in GSE5258) (Lamb et al., 2006). Principal component analysis was used to analyze changes in gene expression after treatment with Treg cell enhancers. These results indicated significant commonalities between most of the Treg cell enhancers identified here, with harmine and the retinoic acids generating the most distinct profiles (Figure 1—figure supplement 8). Together, our results prioritize harmine for its favorable phenotypic profile and likelihood of mechanistic novelty, given its distinct properties in our chemoinformatic analyses.


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

Khor B, Gagnon JD, Goel G, Roche MI, Conway KL, Tran K, Aldrich LN, Sundberg TB, Paterson AM, Mordecai S, Dombkowski D, Schirmer M, Tan PH, Bhan AK, Roychoudhuri R, Restifo NP, O'Shea JJ, Medoff BD, Shamji AF, Schreiber SL, Sharpe AH, Shaw SY, Xavier RJ - Elife (2015)

Euclidean distance clustering analysis of gene expression data from cell lines treated with Treg enhancers first analyzed by principal component analysis.DOI:http://dx.doi.org/10.7554/eLife.05920.011
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4441007&req=5

fig1s8: Euclidean distance clustering analysis of gene expression data from cell lines treated with Treg enhancers first analyzed by principal component analysis.DOI:http://dx.doi.org/10.7554/eLife.05920.011
Mentions: The L1000 method had previously been used to generate gene expression data from three different cell lines treated with numerous compounds, including most of the Treg cell enhancers identified here (expression data in GSE5258) (Lamb et al., 2006). Principal component analysis was used to analyze changes in gene expression after treatment with Treg cell enhancers. These results indicated significant commonalities between most of the Treg cell enhancers identified here, with harmine and the retinoic acids generating the most distinct profiles (Figure 1—figure supplement 8). Together, our results prioritize harmine for its favorable phenotypic profile and likelihood of mechanistic novelty, given its distinct properties in our chemoinformatic analyses.

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital, Harvard Medical School, Boston, United States.

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.

No MeSH data available.


Related in: MedlinePlus