Abstract

The quality of the adaptive immune response depends on the differentiation of distinct CD4+ helper T cell subsets, and the magnitude of an immune response is controlled by CD4+Foxp3+ regulatory T cells (Treg cells). However, how a tissue- and cell type–specific suppressor program of Treg cells is mechanistically orchestrated has remained largely unexplored. Through the use of Treg cell–specific gene targeting, we found that the suppression of allergic immune responses in the lungs mediated by T helper type 2 (TH2) cells was dependent on the activity of the protein kinase CK2. Genetic ablation of the β-subunit of CK2 specifically in Treg cells resulted in the proliferation of a hitherto-unexplored ILT3+ Treg cell subpopulation that was unable to control the maturation of IRF4+PD-L2+ dendritic cells required for the development of TH2 responses in vivo.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Accessions

Primary accessions

Gene Expression Omnibus

References

  1. 1.

    , & Control of regulatory T cell development by the transcription factor Foxp3. Science 299, 1057–1061 (2003).

  2. 2.

    et al. Disruption of a new forkhead/winged-helix protein, scurfin, results in the fatal lymphoproliferative disorder of the scurfy mouse. Nat. Genet. 27, 68–73 (2001).

  3. 3.

    et al. X-linked neonatal diabetes mellitus, enteropathy and endocrinopathy syndrome is the human equivalent of mouse scurfy. Nat. Genet. 27, 18–20 (2001).

  4. 4.

    , & Regulatory T cells prevent catastrophic autoimmunity throughout the lifespan of mice. Nat. Immunol. 8, 191–197 (2007).

  5. 5.

    & The Foxp3+ regulatory T cell: a jack of all trades, master of regulation. Nat. Immunol. 9, 239–244 (2008).

  6. 6.

    Kinase inhibitors: a new class of antirheumatic drugs. Drug. Des. Devel. Ther. 6, 245–250 (2012).

  7. 7.

    , & CK2 and its role in Wnt and NF-kB signaling: linking development and cancer. Cell. Mol. Life Sci. 66, 1850–1857 (2009).

  8. 8.

    , , , & Protein kinase CK2 in health and disease. Cell. Mol. Life Sci. 66, 1858–1867 (2009).

  9. 9.

    et al. CK2 as a positive regulator of Wnt signalling and tumourigenesis. Mol. Cell. Biochem. 274, 63–67 (2005).

  10. 10.

    et al. Disruption of the regulatory β subunit of protein kinase CK2 in mice leads to a cell-autonomous defect and early embryonic lethality. Mol. Cell. Biol. 23, 908–915 (2003).

  11. 11.

    et al. CTLA-4 control over Foxp3+ regulatory T cell function. Science 322, 271–275 (2008).

  12. 12.

    et al. IL-4-induced transcription factor NFIL3/E4BP4 controls IgE class switching. Proc. Natl. Acad. Sci. USA 107, 821–826 (2010).

  13. 13.

    et al. CK2 functionally interacts with AKT/PKB to promote the β-catenin-dependent expression of survivin and enhance cell survival. Mol. Cell. Biochem. 356, 127–132 (2011).

  14. 14.

    CK2 Phosphorylation of the armadillo repeat region of β-catenin potentiates Wnt signaling. J. Biol. Chem. 278, 24018–24025 (2003).

  15. 15.

    Endogenous protein kinase CK2 participates in Wnt signaling in mammary epithelial cells. J. Biol. Chem. 275, 23790–23797 (2000).

  16. 16.

    et al. Phosphorylation of AKT/PKB by CK2 is necessary for the AKT-dependent up-regulation of β-catenin transcriptional activity. J. Cell. Physiol. 226, 1953–1959 (2011).

  17. 17.

    et al. Vitamin D is a multilevel repressor of Wnt/β-catenin signaling in cancer cells. Cancers 5, 1242–1260 (2013).

  18. 18.

    et al. Maternal vitamin D intake during pregnancy increases gene expression of ILT3 and ILT4 in cord blood. Clin. Exp. Allergy 40, 786–794 (2010).

  19. 19.

    , , & gp49B1 inhibits IgE-initiated mast cell activation through both immunoreceptor tyrosine-based inhibitory motifs, recruitment of src homology 2 domain-containing phosphatase-1, and suppression of early and late calcium mobilization. J. Biol. Chem. 274, 5791–5796 (1999).

  20. 20.

    SHP-1 and SHP-2 in T cells: two phosphatases functioning at many levels. Immunol. Rev. 228, 342–359 (2009).

  21. 21.

    et al. T cell receptor signal strength in Treg and iNKT cell development demonstrated by a novel fluorescent reporter mouse. J. Exp. Med. 208, 1279–1289 (2011).

  22. 22.

    et al. Nr4a receptors are essential for thymic regulatory T cell development and immune homeostasis. Nat. Immunol. 14, 230–237 (2013).

  23. 23.

    et al. Control of T Helper 2 Responses by Transcription Factor IRF4-Dependent Dendritic Cells. Immunity 39, 722–732 (2013).

  24. 24.

    et al. Transcription factor IRF4 drives dendritic cells to promote Th2 differentiation. Nat. Commun. 4, 2990 (2013).

  25. 25.

    Naturally arising CD4+ regulatory t cells for immunologic self-tolerance and negative control of immune responses. Annu. Rev. Immunol. 22, 531–562 (2004).

  26. 26.

    , & Regulatory T cell therapy as individualized medicine for asthma and allergy. Curr. Opin. Allergy Clin. Immunol. 7, 535–541 (2007).

  27. 27.

    et al. Instruction of distinct CD4 T helper cell fates by different notch ligands on antigen-presenting cells. Cell 117, 515–526 (2004).

  28. 28.

    et al. Direct regulation of Gata3 expression determines the T helper differentiation potential of Notch. Immunity 27, 89–99 (2007).

  29. 29.

    et al. Regulatory T-cell suppressor program co-opts transcription factor IRF4 to control TH2 responses. Nature 458, 351–356 (2009).

  30. 30.

    et al. Extrathymically generated regulatory T cells control mucosal TH2 inflammation. Nature 482, 395–399 (2012).

  31. 31.

    , & Expression of Helios in peripherally induced Foxp3+ regulatory T cells. J. Immunol. 188, 976–980 (2012).

  32. 32.

    Stability of regulatory T-cell lineage. Adv. Immunol. 112, 1–24 (2011).

  33. 33.

    & One-thousand-and-one substrates of protein kinase CK2? FASEB J. 17, 349–368 (2003).

  34. 34.

    , , , & The protein tyrosine phosphatase SHP-1 modulates the suppressive activity of regulatory T cells. J. Immunol. 185, 6115–6127 (2010).

  35. 35.

    et al. Interaction of T-cell and antigen presenting cell co-stimulatory genes in childhood IgE. Eur. Respir. J. 35, 54–63 (2009).

  36. 36.

    , & Protein kinase CK2 inhibitors: a patent review. Expert Opin. Ther. Pat. 22, 1081–1097 (2012).

  37. 37.

    et al. Selective depletion of Foxp3+ regulatory T cells induces a scurfy-like disease. J. Exp. Med. 204, 57–63 (2007).

  38. 38.

    et al. Requirement for the transcription factor LSIRF/IRF4 for mature B and T lymphocyte function. Science 275, 540–543 (1997).

  39. 39.

    et al. Induction of strong and persistent MelanA/MART-1-specific immune responses by adjuvant dendritic cell-based vaccination of stage II melanoma patients. Int. J. Cancer 118, 2617–2627 (2006).

  40. 40.

    , , & Release of dendritic cells from cognate CD4+ T-cell recognition results in impaired peripheral tolerance and fatal cytotoxic T-cell mediated autoimmunity. Proc. Natl. Acad. Sci. USA 109, 9059–9064 (2012).

  41. 41.

    , , , & Phenotypic and functional characterization of CD11c+ dendritic cell population in mouse Peyer's patches. Eur. J. Immunol. 26, 1801–1806 (1996).

  42. 42.

    et al. NFATc2 and NFATc3 transcription factors play a crucial role in suppression of CD4+ T lymphocytes by CD4+CD25+ regulatory T cells. J. Exp. Med. 201, 181–187 (2005).

  43. 43.

    et al. Infectious tolerance: human CD25+ regulatory T cells convey suppressor activity to conventional CD4+ T helper cells. J. Exp. Med. 196, 255–260 (2002).

  44. 44.

    et al. Regulatory T cells more effectively suppress Th1-induced airway inflammation compared with Th2. J. Immunol. 186, 2238–2244 (2011).

  45. 45.

    et al. Kinome profiling for studying lipopolysaccharide signal transduction in human peripheral blood mononuclear cells. J. Biol. Chem. 279, 49206–49213 (2004).

  46. 46.

    et al. Interferon-regulatory factor 4 is essential for the developmental program of T helper 9 cells. Immunity 33, 192–202 (2010).

  47. 47.

    , , , & Phenotypically distinct subsets of CD4+ T cells induce or protect from chronic intestinal inflammation in C. B-17 scid mice. Int. Immunol. 5, 1461–1471 (1993).

  48. 48.

    et al. In vivo expansion of T reg cells with IL-2-mAb complexes: induction of resistance to EAE and long-term acceptance of islet allografts without immunosuppression. J. Exp. Med. 206, 751–760 (2009).

  49. 49.

    , , & Pathogenic nematodes suppress humoral responses to third-party antigens in vivo by IL-10-mediated interference with Th cell function. J. Immunol. 187, 4088–4099 (2011).

Download references

Acknowledgements

We thank S. Sakaguchi (Osaka University) for BALB/c Foxp3-IRES-Cre mice; B. Boldyreff (University of Southern Denmark) for Csnk2bfl mice on the C57BL/6 background; T. Sparwasser (TWINCORE) for C57BL/6 DEREG mice; K.A. Hogquist (University of Minnesota) for Nur77GFP mice; M. Lohoff (Philipps University Marburg) for C57BL/6 Irf4−/− mice; H.C. Probst (University Medical Center Mainz) for Ly5.1+ C57BL/6 mice; A. Waisman (University Medical Center Mainz) for CD90.1+ C57BL/6 mice; A. Nikolaev and S. Fischer for technical help, and D. O'Neill for critical reading of the manuscript. Supported by Deutsche Forschungsgemeinschaft (DFG BO 3306/1-1, SCHM 1014/7-1, SCHM 1014/5-1, SFB TR128 projects B4 (T.Bop. and F.Z.), A7 (A.W.) and A9 (H.J.), SFB 1066 projects B1 (E.S.) and B8 (T.Bop.), and BR 3754/2-1 (I.H. and M.B.)), International Graduate School of Immunotherapy (GRK 1043 project C4 (E.S. and T.Bop.)) and Forschungszentrum Immunologie of the University Medical Center of the Johannes Gutenberg-University Mainz (E.S. and T.Bop.).

Author information

Author notes

    • Edgar Schmitt
    •  & Tobias Bopp

    These authors jointly directed this work.

Affiliations

  1. Institute for Immunology, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany.

    • Alexander Ulges
    • , Matthias Klein
    • , Bastian Gerlitzki
    • , Markus Hoffmann
    • , Nadine Grebe
    • , Valérie Staudt
    • , Natascha Stergiou
    • , Toszka Bohn
    • , Till-Julius Brühl
    • , Sabine Muth
    • , Hajime Yurugi
    • , Krishnaraj Rajalingam
    • , Hans-Christian Probst
    • , Hansjörg Schild
    • , Edgar Schmitt
    •  & Tobias Bopp
  2. Department of Pulmonary Medicine, III. Medical Clinic of the University Medical Center, Johannes Gutenberg-University Mainz, Mainz, Germany.

    • Sebastian Reuter
  3. Dermatology, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany.

    • Iris Bellinghausen
    • , Andrea Tuettenberg
    • , Susanne Hahn
    •  & Helmut Jonuleit
  4. Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany.

    • Sonja Reißig
    •  & Ari Waisman
  5. Department of Immunology and Virology, Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany.

    • Irma Haben
    •  & Minka Breloer
  6. Department of Neurology, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany.

    • Frauke Zipp
  7. Experimentelle Stammzelltransplantation der Medizinische Klinik und Poliklinik II, Zentrum für Experimentelle Molekulare Medizin, Julius-Maximilians-Universität Würzburg, Würzburg, Germany.

    • Andreas Beilhack
  8. INSERM, U823, Université Joseph Fourier-Grenoble1, Institut Albert Boniot, Faculté de Médecine, Domaine de la Merci, La Tronche, France.

    • Thierry Buchou
  9. INSERM U1036, Institute de Recherches en Technologies et Sciences pour le Vivant/Biologie du Cancer et de l'Infection, Commissariat à l'Énergie Atomique et aux Énerigies Alternatives Grenoble, Grenoble, France.

    • Odile Filhol-Cochet
  10. KinaseDetect, Aarslev, Denmark.

    • Brigitte Boldyreff

Authors

  1. Search for Alexander Ulges in:

  2. Search for Matthias Klein in:

  3. Search for Sebastian Reuter in:

  4. Search for Bastian Gerlitzki in:

  5. Search for Markus Hoffmann in:

  6. Search for Nadine Grebe in:

  7. Search for Valérie Staudt in:

  8. Search for Natascha Stergiou in:

  9. Search for Toszka Bohn in:

  10. Search for Till-Julius Brühl in:

  11. Search for Sabine Muth in:

  12. Search for Hajime Yurugi in:

  13. Search for Krishnaraj Rajalingam in:

  14. Search for Iris Bellinghausen in:

  15. Search for Andrea Tuettenberg in:

  16. Search for Susanne Hahn in:

  17. Search for Sonja Reißig in:

  18. Search for Irma Haben in:

  19. Search for Frauke Zipp in:

  20. Search for Ari Waisman in:

  21. Search for Hans-Christian Probst in:

  22. Search for Andreas Beilhack in:

  23. Search for Thierry Buchou in:

  24. Search for Odile Filhol-Cochet in:

  25. Search for Brigitte Boldyreff in:

  26. Search for Minka Breloer in:

  27. Search for Helmut Jonuleit in:

  28. Search for Hansjörg Schild in:

  29. Search for Edgar Schmitt in:

  30. Search for Tobias Bopp in:

Contributions

A.U. performed and analyzed most experiments; M.K., B.G., M.H., N.G., V.S., N.S., T.Boh., T.-J.B., S.M., H.Y., K.R. and H.-C.P. helped design and perform some experiments; S.Reu. helped to perform and analyze mouse asthma experiments; M.K. conducted RNA-seq experiments; I.B., A.T., S.H., H.J. performed experiments involving human T cells; S.Rei. performed and analyzed adoptive transfer colitis experiments; I.H. and M.B. performed and analyzed nematode infection experiments; F.Z., A.W., A.B., T.Bu., O.F.-C., B.B. and H.S. helped design, analyze and interpret experiments; E.S. and T.Bop. supervised the project, designed experiments and wrote the manuscript; and all authors reviewed and approved the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Tobias Bopp.

Integrated supplementary information

Supplementary information

PDF files

  1. 1.

    Supplementary Text and Figures

    Supplementary Figures 1–8

Excel files

  1. 1.

    Supplementary Table 1

    Antibodies.

About this article

Publication history

Received

Accepted

Published

DOI

https://doi.org/10.1038/ni.3083

Further reading