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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

Effects of harmine treatment in vivo on T cell populations.Mice were administered either intranasal harmine HCl (blue) or water (gray). T cell populations in thoracic lymph nodes were quantitated as shown, demonstrating relative percentages (above) and absolute numbers (below). All statistically significant differences are indicated, **p < 0.01, ***p < 0.001, Student's t-test with Holm-Sidak correction.DOI:http://dx.doi.org/10.7554/eLife.05920.013
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fig2s1: Effects of harmine treatment in vivo on T cell populations.Mice were administered either intranasal harmine HCl (blue) or water (gray). T cell populations in thoracic lymph nodes were quantitated as shown, demonstrating relative percentages (above) and absolute numbers (below). All statistically significant differences are indicated, **p < 0.01, ***p < 0.001, Student's t-test with Holm-Sidak correction.DOI:http://dx.doi.org/10.7554/eLife.05920.013

Mentions: The observation that harmine promotes the differentiation of Treg cells, at least in vitro, that appear fully functional raises the interesting hypothesis that treatment with harmine itself could attenuate inflammation in vivo. Rapid first pass metabolism (<2 hr) consistent with prior reports confounded the interpretation of systemic delivery experiments (Callaway et al., 1999). Reasoning that application of harmine to mucosal surfaces might allow for relatively prolonged local presence, we treated mice with harmine intranasally for 5 days and examined the effect on Treg cells in the draining lymph nodes. Compared to mice treated only with vehicle (water), mice treated with harmine exhibited a statistically significant increase (∼20%) in the frequency of Treg cells in the draining thoracic lymph nodes; increases in absolute numbers of effector T cell subsets did not reach statistical significance (Figure 2F and Figure 2—figure supplement 1). Analyses of dendritic cell populations did not show any effect of treatment with harmine on expression of Treg-relevant costimulatory molecules, consistent with the notion that harmine predominantly acts directly on CD4+ T cells to affect Treg/Th17 differentiation in this model (Figure 2—figure supplement 2). To determine if this pro-Treg effect might impact inflammation, we adapted the model of airway inflammation described above, where sensitivity to ovalbumin is induced by immunization. Intranasal administration of ovalbumin 5–7 days prior to immunization attenuated the airway inflammation induced by subsequent intratracheal challenge (Figure 2G). This finding supports the notion that exogenous signals can modulate the inflammatory response mounted at the time of immunization. Strikingly, intranasal administration of only harmine during this window inhibited airway inflammation at least as potently as tolerization with ovalbumin (Figure 2G).


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)

Effects of harmine treatment in vivo on T cell populations.Mice were administered either intranasal harmine HCl (blue) or water (gray). T cell populations in thoracic lymph nodes were quantitated as shown, demonstrating relative percentages (above) and absolute numbers (below). All statistically significant differences are indicated, **p < 0.01, ***p < 0.001, Student's t-test with Holm-Sidak correction.DOI:http://dx.doi.org/10.7554/eLife.05920.013
© Copyright Policy
Related In: Results  -  Collection

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

fig2s1: Effects of harmine treatment in vivo on T cell populations.Mice were administered either intranasal harmine HCl (blue) or water (gray). T cell populations in thoracic lymph nodes were quantitated as shown, demonstrating relative percentages (above) and absolute numbers (below). All statistically significant differences are indicated, **p < 0.01, ***p < 0.001, Student's t-test with Holm-Sidak correction.DOI:http://dx.doi.org/10.7554/eLife.05920.013
Mentions: The observation that harmine promotes the differentiation of Treg cells, at least in vitro, that appear fully functional raises the interesting hypothesis that treatment with harmine itself could attenuate inflammation in vivo. Rapid first pass metabolism (<2 hr) consistent with prior reports confounded the interpretation of systemic delivery experiments (Callaway et al., 1999). Reasoning that application of harmine to mucosal surfaces might allow for relatively prolonged local presence, we treated mice with harmine intranasally for 5 days and examined the effect on Treg cells in the draining lymph nodes. Compared to mice treated only with vehicle (water), mice treated with harmine exhibited a statistically significant increase (∼20%) in the frequency of Treg cells in the draining thoracic lymph nodes; increases in absolute numbers of effector T cell subsets did not reach statistical significance (Figure 2F and Figure 2—figure supplement 1). Analyses of dendritic cell populations did not show any effect of treatment with harmine on expression of Treg-relevant costimulatory molecules, consistent with the notion that harmine predominantly acts directly on CD4+ T cells to affect Treg/Th17 differentiation in this model (Figure 2—figure supplement 2). To determine if this pro-Treg effect might impact inflammation, we adapted the model of airway inflammation described above, where sensitivity to ovalbumin is induced by immunization. Intranasal administration of ovalbumin 5–7 days prior to immunization attenuated the airway inflammation induced by subsequent intratracheal challenge (Figure 2G). This finding supports the notion that exogenous signals can modulate the inflammatory response mounted at the time of immunization. Strikingly, intranasal administration of only harmine during this window inhibited airway inflammation at least as potently as tolerization with ovalbumin (Figure 2G).

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