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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

Effect of compounds (LD50/EC50 < 2) on Th differentiation.Dose-response curves showing compound effect on fractional enhancement of Treg (blue), Th1 (orange), and Th17 (red) lineages.DOI:http://dx.doi.org/10.7554/eLife.05920.007
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fig1s4: Effect of compounds (LD50/EC50 < 2) on Th differentiation.Dose-response curves showing compound effect on fractional enhancement of Treg (blue), Th1 (orange), and Th17 (red) lineages.DOI:http://dx.doi.org/10.7554/eLife.05920.007

Mentions: The compounds prioritized by our efforts described above were retested (using Treglow conditions) at 8 doses that typically covered over a 1000-fold difference in concentration, allowing us to capture more optimal concentrations at which a compound might work (Figure 1B). In order to filter for compounds that only enhance Treg cell differentiation, these compounds were also tested under Th1low and Th17low conditions to quantitate their ability to enhance differentiation of pro-inflammatory lineages. Our results also consolidate and validate that the previously described Treg enhancers, including the statins, retinoic acids and artemisinin, specifically enhance Treg differentiation. Simultaneously testing multiple Th lineages and drug concentrations allows a more complete characterization of the effects of a compound on Th differentiation and furthers mechanistic conclusions. We identified 14 compounds hitherto unreported to specifically enhance differentiation of Treg, but neither Th1 nor Th17, cells (Figure 1B,C and Figure 1—figure supplement 4).


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)

Effect of compounds (LD50/EC50 < 2) on Th differentiation.Dose-response curves showing compound effect on fractional enhancement of Treg (blue), Th1 (orange), and Th17 (red) lineages.DOI:http://dx.doi.org/10.7554/eLife.05920.007
© Copyright Policy
Related In: Results  -  Collection

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

fig1s4: Effect of compounds (LD50/EC50 < 2) on Th differentiation.Dose-response curves showing compound effect on fractional enhancement of Treg (blue), Th1 (orange), and Th17 (red) lineages.DOI:http://dx.doi.org/10.7554/eLife.05920.007
Mentions: The compounds prioritized by our efforts described above were retested (using Treglow conditions) at 8 doses that typically covered over a 1000-fold difference in concentration, allowing us to capture more optimal concentrations at which a compound might work (Figure 1B). In order to filter for compounds that only enhance Treg cell differentiation, these compounds were also tested under Th1low and Th17low conditions to quantitate their ability to enhance differentiation of pro-inflammatory lineages. Our results also consolidate and validate that the previously described Treg enhancers, including the statins, retinoic acids and artemisinin, specifically enhance Treg differentiation. Simultaneously testing multiple Th lineages and drug concentrations allows a more complete characterization of the effects of a compound on Th differentiation and furthers mechanistic conclusions. We identified 14 compounds hitherto unreported to specifically enhance differentiation of Treg, but neither Th1 nor Th17, cells (Figure 1B,C and Figure 1—figure supplement 4).

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