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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.


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Schematic of analytic and hit-calling pipeline.DOI:http://dx.doi.org/10.7554/eLife.05920.006
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fig1s3: Schematic of analytic and hit-calling pipeline.DOI:http://dx.doi.org/10.7554/eLife.05920.006

Mentions: To find small molecules that enhance Treg cell differentiation, Treglow conditions were used to screen 3281 compounds comprising FDA-approved drugs and tool compounds with known mechanisms (Shaw et al., 2013). Our studies revealed a previously unreported negative correlation between the number of live cells in culture and the percentage of FOXP3+ cells in Treglow conditions, not observed in Treghi, Th1low/hi or Th17low/hi conditions (Figure 1—figure supplement 2). Because the compounds tested exhibit variable effects on cellularity, we accounted for corresponding effects on Treg cell differentiation using a linear regression model (Figure 1—figure supplement 3). Numerous compounds previously reported to enhance Treg cell differentiation were recovered, including the hypolipidemic statins (lovastatin and simvastatin), artemisinin and ATRA as well as related retinoic acids (9-cis retinoic acid and 13-cis retinoic acid), validating our experimental approach (Coombes et al., 2007; Mucida et al., 2007; Sun et al., 2007; Kagami et al., 2009; Kim et al., 2010; Zhao et al., 2012). The fractional enhancement of the weakest of these known enhancers (artemisinin, 0.3) was used as a minimum threshold to find all compounds that enhance Treg cell differentiation at least as strongly. By this criterion, 70 compounds were selected for retesting.


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)

Schematic of analytic and hit-calling pipeline.DOI:http://dx.doi.org/10.7554/eLife.05920.006
© Copyright Policy
Related In: Results  -  Collection

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

fig1s3: Schematic of analytic and hit-calling pipeline.DOI:http://dx.doi.org/10.7554/eLife.05920.006
Mentions: To find small molecules that enhance Treg cell differentiation, Treglow conditions were used to screen 3281 compounds comprising FDA-approved drugs and tool compounds with known mechanisms (Shaw et al., 2013). Our studies revealed a previously unreported negative correlation between the number of live cells in culture and the percentage of FOXP3+ cells in Treglow conditions, not observed in Treghi, Th1low/hi or Th17low/hi conditions (Figure 1—figure supplement 2). Because the compounds tested exhibit variable effects on cellularity, we accounted for corresponding effects on Treg cell differentiation using a linear regression model (Figure 1—figure supplement 3). Numerous compounds previously reported to enhance Treg cell differentiation were recovered, including the hypolipidemic statins (lovastatin and simvastatin), artemisinin and ATRA as well as related retinoic acids (9-cis retinoic acid and 13-cis retinoic acid), validating our experimental approach (Coombes et al., 2007; Mucida et al., 2007; Sun et al., 2007; Kagami et al., 2009; Kim et al., 2010; Zhao et al., 2012). The fractional enhancement of the weakest of these known enhancers (artemisinin, 0.3) was used as a minimum threshold to find all compounds that enhance Treg cell differentiation at least as strongly. By this criterion, 70 compounds were selected for retesting.

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