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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 harmine on absolute numbers of Th17 cells.***p < 0.001, Student's t-test.DOI:http://dx.doi.org/10.7554/eLife.05920.017
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fig3s2: Effect of harmine on absolute numbers of Th17 cells.***p < 0.001, Student's t-test.DOI:http://dx.doi.org/10.7554/eLife.05920.017

Mentions: Our results demonstrate that harmine is a novel, potent, and specific enhancer of Treg cell differentiation with physiologically relevant effects (Figures 1B, 3A). In addition to its pro-Treg effect, harmine strongly inhibits Th17 cell differentiation (Figure 3A). Notably, even in pro-inflammatory Th17low or Th17hi conditions, harmine modestly promotes the paradoxical differentiation of Treg cells approximately twofold (Figure 3A). At the doses used, harmine does not significantly affect culture cellularity, unlike ATRA and rapamycin (Figure 3B). This observation is further substantiated by CFSE studies of cellular proliferation, which show that harmine causes a modest 24% reduction in proliferating cells at day 3 that falls to undetectable levels by day 4, less than half the reduction caused by rapamycin (Figure 3—figure supplement 1). Accordingly, harmine enhances absolute numbers of Treg cells to levels approaching Treghi conditions and decreases absolute numbers of Th17 cells (Figure 3B and Figure 3—figure supplement 2). Importantly, similar effects are observed using human CD4+ T cells, with addition of harmine potently enhancing both percentage and absolute numbers of Treg cells beyond even Treghi conditions (Figure 3C). These findings underscore the physiologic relevance of harmine-related pathways to human Th differentiation.10.7554/eLife.05920.015Figure 3.Harmine's effects on canonical Treg/Th17 pathways.


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 harmine on absolute numbers of Th17 cells.***p < 0.001, Student's t-test.DOI:http://dx.doi.org/10.7554/eLife.05920.017
© Copyright Policy
Related In: Results  -  Collection

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

fig3s2: Effect of harmine on absolute numbers of Th17 cells.***p < 0.001, Student's t-test.DOI:http://dx.doi.org/10.7554/eLife.05920.017
Mentions: Our results demonstrate that harmine is a novel, potent, and specific enhancer of Treg cell differentiation with physiologically relevant effects (Figures 1B, 3A). In addition to its pro-Treg effect, harmine strongly inhibits Th17 cell differentiation (Figure 3A). Notably, even in pro-inflammatory Th17low or Th17hi conditions, harmine modestly promotes the paradoxical differentiation of Treg cells approximately twofold (Figure 3A). At the doses used, harmine does not significantly affect culture cellularity, unlike ATRA and rapamycin (Figure 3B). This observation is further substantiated by CFSE studies of cellular proliferation, which show that harmine causes a modest 24% reduction in proliferating cells at day 3 that falls to undetectable levels by day 4, less than half the reduction caused by rapamycin (Figure 3—figure supplement 1). Accordingly, harmine enhances absolute numbers of Treg cells to levels approaching Treghi conditions and decreases absolute numbers of Th17 cells (Figure 3B and Figure 3—figure supplement 2). Importantly, similar effects are observed using human CD4+ T cells, with addition of harmine potently enhancing both percentage and absolute numbers of Treg cells beyond even Treghi conditions (Figure 3C). These findings underscore the physiologic relevance of harmine-related pathways to human Th differentiation.10.7554/eLife.05920.015Figure 3.Harmine's effects on canonical Treg/Th17 pathways.

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