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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

Qualitative analyses of genomewide expression in TregHAR-Treg cells.Previously described methods were used to identify similarities between TregHAR-Treg cells and other specialized Treg subsets (Joller et al., 2014). Volcano plots compare relative expression of genes in Treghi-Treg cells and TregHAR-Treg cells. Overlaid are genes of previously identified signatures; red and green reflect genes up- and down-regulated in these signatures respectively. Numbers on the right and left reflect genes that are up- and down-regulated in the indicated comparison respectively with χ2 test p values in the middle.DOI:http://dx.doi.org/10.7554/eLife.05920.020
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fig3s5: Qualitative analyses of genomewide expression in TregHAR-Treg cells.Previously described methods were used to identify similarities between TregHAR-Treg cells and other specialized Treg subsets (Joller et al., 2014). Volcano plots compare relative expression of genes in Treghi-Treg cells and TregHAR-Treg cells. Overlaid are genes of previously identified signatures; red and green reflect genes up- and down-regulated in these signatures respectively. Numbers on the right and left reflect genes that are up- and down-regulated in the indicated comparison respectively with χ2 test p values in the middle.DOI:http://dx.doi.org/10.7554/eLife.05920.020

Mentions: To determine the effect of harmine on gene expression in Treg cells, RNA was isolated from FACS-sorted Treg cells, generated under either TregHAR or Treghi conditions, and analyzed by Illumina microarray (data in GSE67961). These results revealed significant similarity between the expression profiles of Treghi- and TregHAR-Treg cells (Pearson correlation coefficient = 0.95, Figure 3—figure supplement 4). As might be expected from this result, TregHAR-Treg cells showed concordant regulation of previously described canonical Treg cell signature genes (Figure 3F) (Feuerer et al., 2010). We found no evidence of significant similarity to Treg cells specialized to suppress Th1, Th2 or Th17 cells (CXCR3+, IRF4+ and GFP-FOXP3-fusion Treg cells respectively, Figure 3—figure supplement 5) (Joller et al., 2014). However, compared to Treghi-Treg cells, TregHAR-Treg cells showed a bias suggesting increased activation (Figure 3G) (Joller et al., 2014). In addition, flow cytometry studies showed that, after gating on FOXP3+ Treg cells, TregHAR-Treg cells express FOXP3 at levels at least as high as, if not higher than, those of Treghi-Treg cells (Figure 3H). Together, these results suggest that harmine promotes the differentiation of Treg cells that are of similar to superior function as compared to those driven by high levels of TGF-β1 alone.


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)

Qualitative analyses of genomewide expression in TregHAR-Treg cells.Previously described methods were used to identify similarities between TregHAR-Treg cells and other specialized Treg subsets (Joller et al., 2014). Volcano plots compare relative expression of genes in Treghi-Treg cells and TregHAR-Treg cells. Overlaid are genes of previously identified signatures; red and green reflect genes up- and down-regulated in these signatures respectively. Numbers on the right and left reflect genes that are up- and down-regulated in the indicated comparison respectively with χ2 test p values in the middle.DOI:http://dx.doi.org/10.7554/eLife.05920.020
© Copyright Policy
Related In: Results  -  Collection

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

fig3s5: Qualitative analyses of genomewide expression in TregHAR-Treg cells.Previously described methods were used to identify similarities between TregHAR-Treg cells and other specialized Treg subsets (Joller et al., 2014). Volcano plots compare relative expression of genes in Treghi-Treg cells and TregHAR-Treg cells. Overlaid are genes of previously identified signatures; red and green reflect genes up- and down-regulated in these signatures respectively. Numbers on the right and left reflect genes that are up- and down-regulated in the indicated comparison respectively with χ2 test p values in the middle.DOI:http://dx.doi.org/10.7554/eLife.05920.020
Mentions: To determine the effect of harmine on gene expression in Treg cells, RNA was isolated from FACS-sorted Treg cells, generated under either TregHAR or Treghi conditions, and analyzed by Illumina microarray (data in GSE67961). These results revealed significant similarity between the expression profiles of Treghi- and TregHAR-Treg cells (Pearson correlation coefficient = 0.95, Figure 3—figure supplement 4). As might be expected from this result, TregHAR-Treg cells showed concordant regulation of previously described canonical Treg cell signature genes (Figure 3F) (Feuerer et al., 2010). We found no evidence of significant similarity to Treg cells specialized to suppress Th1, Th2 or Th17 cells (CXCR3+, IRF4+ and GFP-FOXP3-fusion Treg cells respectively, Figure 3—figure supplement 5) (Joller et al., 2014). However, compared to Treghi-Treg cells, TregHAR-Treg cells showed a bias suggesting increased activation (Figure 3G) (Joller et al., 2014). In addition, flow cytometry studies showed that, after gating on FOXP3+ Treg cells, TregHAR-Treg cells express FOXP3 at levels at least as high as, if not higher than, those of Treghi-Treg cells (Figure 3H). Together, these results suggest that harmine promotes the differentiation of Treg cells that are of similar to superior function as compared to those driven by high levels of TGF-β1 alone.

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