The kinase DYRK1A reciprocally regulates the differentiation of Th17 and regulatory T cells

Bernard Khor; John D. Gagnon; Gautam Goel; Marly I. Roche; Kara L. Conway; Khoa Tran; Leslie N. Aldrich; Thomas B. Sundberg; Alison M. Paterson; Scott Mordecai; David Dombkowski; Melanie Schirmer; Pauline H. Tan; Atul K. Bhan; Rahul Roychoudhuri; Nicholas P. Restifo; John J. O’Shea; Benjamin D. Medoff; Alykhan F. Shamji; Stuart L. Schreiber; Arlene H. Sharpe; Stanley Y. Shaw; Ramnik J. Xavier

doi:10.7554/eLife.05920

The kinase DYRK1A reciprocally regulates the differentiation of Th17 and regulatory T cells

Bernard Khor, John D. Gagnon, Gautam Goel, Marly I. Roche, Kara L. Conway, Khoa Tran, Leslie N. Aldrich, Thomas B. Sundberg, Alison M. Paterson, Scott Mordecai, David Dombkowski, Melanie Schirmer, Pauline H. Tan, Atul K. Bhan, Rahul Roychoudhuri, Nicholas P. Restifo, John J. O’Shea, Benjamin D. Medoff, Alykhan F. Shamji, Stuart L. SchreiberArlene H. Sharpe, Stanley Y. Shaw, Ramnik J. Xavier

Research output: Contribution to journal › Article › peer-review

48 Scopus citations

Abstract

The balance between Th17 and T regulatory (T_reg) cells critically modulates immune homeostasis, with an inadequate T_reg response contributing to inflammatory disease. Using an unbiased chemical biology approach, we identified a novel role for the dual specificity tyrosinephosphorylation- 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 T_reg 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.

Original language	English
Article number	e05920
Pages (from-to)	1-27
Number of pages	27
Journal	eLife
Volume	4
Issue number	MAY
DOIs	https://doi.org/10.7554/eLife.05920
State	Published - 22 May 2015
Externally published	Yes

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10.7554/eLife.05920

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Khor, B., Gagnon, J. D., Goel, G., Roche, M. I., Conway, K. L., Tran, K., Aldrich, L. N., Sundberg, T. B., Paterson, A. M., Mordecai, S., Dombkowski, D., Schirmer, M., Tan, P. H., Bhan, A. K., Roychoudhuri, R., Restifo, N. P., O’Shea, J. J., Medoff, B. D., Shamji, A. F., ... Xavier, R. J. (2015). The kinase DYRK1A reciprocally regulates the differentiation of Th17 and regulatory T cells. eLife, 4(MAY), 1-27. Article e05920. https://doi.org/10.7554/eLife.05920

@article{029059da5cdf4144ab77e19f8f5b5b1a,

title = "The kinase DYRK1A reciprocally regulates the differentiation of Th17 and regulatory T cells",

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 tyrosinephosphorylation- 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.",

author = "Bernard Khor and Gagnon, {John D.} and Gautam Goel and Roche, {Marly I.} and Conway, {Kara L.} and Khoa Tran and Aldrich, {Leslie N.} and Sundberg, {Thomas B.} and Paterson, {Alison M.} and Scott Mordecai and David Dombkowski and Melanie Schirmer and Tan, {Pauline H.} and Bhan, {Atul K.} and Rahul Roychoudhuri and Restifo, {Nicholas P.} and O{\textquoteright}Shea, {John J.} and Medoff, {Benjamin D.} and Shamji, {Alykhan F.} and Schreiber, {Stuart L.} and Sharpe, {Arlene H.} and Shaw, {Stanley Y.} and Xavier, {Ramnik J.}",

year = "2015",

month = may,

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doi = "10.7554/eLife.05920",

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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 2015, 'The kinase DYRK1A reciprocally regulates the differentiation of Th17 and regulatory T cells', eLife, vol. 4, no. MAY, e05920, pp. 1-27. https://doi.org/10.7554/eLife.05920

TY - JOUR

T1 - The kinase DYRK1A reciprocally regulates the differentiation of Th17 and regulatory T cells

AU - Khor, Bernard

AU - Gagnon, John D.

AU - Goel, Gautam

AU - Roche, Marly I.

AU - Conway, Kara L.

AU - Tran, Khoa

AU - Aldrich, Leslie N.

AU - Sundberg, Thomas B.

AU - Paterson, Alison M.

AU - Mordecai, Scott

AU - Dombkowski, David

AU - Schirmer, Melanie

AU - Tan, Pauline H.

AU - Bhan, Atul K.

AU - Roychoudhuri, Rahul

AU - Restifo, Nicholas P.

AU - O’Shea, John J.

AU - Medoff, Benjamin D.

AU - Shamji, Alykhan F.

AU - Schreiber, Stuart L.

AU - Sharpe, Arlene H.

AU - Shaw, Stanley Y.

AU - Xavier, Ramnik J.

PY - 2015/5/22

Y1 - 2015/5/22

N2 - 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 tyrosinephosphorylation- 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.

AB - 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 tyrosinephosphorylation- 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.

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U2 - 10.7554/eLife.05920

DO - 10.7554/eLife.05920

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AN - SCOPUS:84930671852

SN - 2050-084X

VL - 4

SP - 1

EP - 27

JO - eLife

JF - eLife

IS - MAY

M1 - e05920

ER -

The kinase DYRK1A reciprocally regulates the differentiation of Th17 and regulatory T cells

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