Skip to main content
SpringerLink
Log in

β2-adrenergic stimulation of dendritic cells favors IL-10 secretion by CD4+ T cells

  • Original Article
  • Published:
Immunologic Research Aims and scope Submit manuscript

Abstract

Adrenergic receptor agonists and antagonists are extensively used as drugs in medicine for a broad spectrum of indications. We examined the consequences of β2-adrenergic stimulation of murine dendritic cells (DCs) on CD4+ T cell activation. We demonstrated in vitro that treatment of LPS-matured DCs with the β2-agonist salbutamol reduced their ability to trigger OT-II T cell proliferation specific for ovalbumin antigen. Salbutamol also induced a decrease in MHC class II molecule expression by DC through Gi protein activation. Co-culture of CD4+ T cells with salbutamol-conditioned mature DC impaired TNFα and IL-6 secretion while preserving IL-10 production by T cells. Using a vaccination protocol in mice, we showed that salbutamol favored IL-10-producing CD4+ T cells. None of these effects was observed when working with β2-adrenoreceptor deficient mice. Finally, we suggest that β2-adrenergic stimulation of DC could be an interesting way to shape CD4+ T cell responses for the purposes of immunotherapy.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Bellinger DL, Lorton D. Autonomic regulation of cellular immune function. Auton Neurosci-Basic Clin. 2014;182:15–41.

    Article  CAS  Google Scholar 

  2. Maestroni GJM, Mazzola P. Langerhans cells beta 2-adrenoceptors: role in migration, cytokine production, Th priming and contact hypersensitivity. J Neuroimmunol. 2003;144(1–2):91–9.

    Article  CAS  PubMed  Google Scholar 

  3. Takenaka MC, Araujo LP, Maricato JT, Nascimento VM, Guereschi MG, Rezende RM, et al. Norepinephrine controls effector T cell differentiation through beta 2-adrenergic receptor-mediated inhibition of NF-kappa B and AP-1 in dendritic cells. J Immunol. 2016;196(2):637–44.

    Article  CAS  PubMed  Google Scholar 

  4. Hilkens CMU, Isaacs JD, Thomson AW. Development of dendritic cell-based immunotherapy for autoimmunity. Int Rev Immunol. 2010;29(2):156–83.

    Article  CAS  PubMed  Google Scholar 

  5. Pricet JD, Tarbell KV. The role of dendritic cell subsets and innate immunity in the pathogenesis of type 1 diabetes and other autoimmune diseases. Front Immunol. 2015;6

  6. Giannoukakis N, Phillips B, Finegold D, Harnaha J, Trucco M. Phase 1 (safety) study of autologous tolerogenic dendritic cells in type 1 diabetic patients. Diabetes Care. 2011;34(9):2026–32.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Panina-Bordignon P, Mazzeo D, DiLucia P, Dambrosio D, Lang R, Fabbri L, et al. Beta(2)-agonists prevent Th1 development by selective inhibition of interleukin 12. J Clin Investig. 1997;100(6):1513–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Cobelens PM, Kavelaars A, Vroon A, Ringeling M, van der Zee R, van Eden W, et al. The beta(2)-adrenergic agonist salbutamol potentiates oral induction of tolerance, suppressing adjuvant arthritis and antigen-specific immunity. J Immunol. 2002;169(9):5028–35.

    Article  PubMed  Google Scholar 

  9. Lutz M. Induction of CD4+ regulatory and polarized effector/helper T cells by dendritic cells. Immune Network. 2016;16(1):13–25.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Herve J, Dubreil L, Tardif V, Terme M, Pogu S, Anegon I, et al. Beta 2-Adrenoreceptor agonist inhibits antigen cross-presentation by dendritic cells. J Immunol. 2013;190(7):3163–71.

    Article  CAS  PubMed  Google Scholar 

  11. Nishii M, Inomata T, Niwano H, Takehana H, Takeuchi I, Nakano H, et al. Beta 2-adrenergic agonists suppress rat autoimmune myocarditis potential role of beta 2-adrenergic stimulants as new therapeutic agents for myocarditis. Circulation. 2006;114(9):936–44.

    Article  CAS  PubMed  Google Scholar 

  12. Nijhuis LE, Olivier BJ, Dhawan S, Hilbers FW, Boon L, Wolkers MC, et al. Adrenergic beta 2 receptor activation stimulates anti-inflammatory properties of dendritic cells in vitro. Plos One. 2014;9(1)

  13. Takayanagi Y, Osawa S, Ikuma M, Takagaki K, Zhang J, Hamaya Y, et al. Norepinephrine suppresses IFN-gamma and TNF-alpha production by murine intestinal intraepithelial lymphocytes via the beta(1) adrenoceptor. J Neuroimmunol. 2012;245(1–2):66–74.

    Article  CAS  PubMed  Google Scholar 

  14. Kato G, Takahashi K, Tashiro H, Kurata K, Shirai H, Kimura S, et al. Beta 2 adrenergic agonist attenuates house dust mite-induced allergic airway inflammation through dendritic cells. BMC Immunol. 2014:15.

  15. Manni M, Granstein RD, Maestroni G. Beta 2-adrenergic agonists bias TLR-2 and NOD2 activated dendritic cells towards inducing an IL-17 immune response. Cytokine. 2011;55(3):380–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Kim B-J, Jones HP. Epinephrine-primed murine bone marrow-derived dendritic cells facilitate production of IL-17A and IL-4 but not IFN-gamma by CD4(+) T cells. Brain Behav Immun. 2010;24(7):1126–36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Helft J, Bottcher J, Chakravarty P, Zelenay S, Huotari J, Schraml BU, et al. GM-CSF mouse bone marrow cultures comprise a heterogeneous population of CD11c(+) MHCII(+) macrophages and dendritic cells. Immunity. 2015;42(6):1197–211.

    Article  CAS  PubMed  Google Scholar 

  18. Poon GFT, Dong YF, Marshall KC, Arif A, Deeg CM, Dosanjh M, et al. Hyaluronan binding identifies a functionally distinct alveolar macrophage-like population in bone marrow-derived dendritic cell cultures. J Immunol. 2015;195(2):632–42.

    Article  CAS  PubMed  Google Scholar 

  19. Lutz MB, Inaba K, Schuler G, Romani N. Still alive and kicking: in-vitro-generated GM-CSF dendritic cells. Immunity. 2016;44(1):1–2.

    Article  CAS  PubMed  Google Scholar 

  20. Helft J, Bottcher JP, Chakravarty P, Zelenay S, Huotari J, Schraml BU, et al. Alive but confused: heterogeneity of CD11c(+) MHC class II+ cells in GM-CSF mouse bone marrow cultures. Immunity. 2016;44(1):3–4.

    Article  CAS  PubMed  Google Scholar 

  21. Chruscinski AJ, Rohrer DK, Schauble E, Desai KH, Bernstein D, Kobilka BK. Targeted disruption of the beta 2 adrenergic receptor gene. J Biol Chem. 1999;274(24):16694–700.

    Article  CAS  PubMed  Google Scholar 

  22. Zal T, Volkmann A, Stockinger B. Mechanisms of tolerance induction in major histocompatibility complex class II-restricted T-cells specific for a blood-borne self-antigen. J Exp Med. 1994;180(6):2089–99.

    Article  CAS  PubMed  Google Scholar 

  23. Lutz MB, Kukutsch N, Ogilvie AL, Rossner S, Koch F, Romani N, et al. An advanced culture method for generating large quantities of highly pure dendritic cells from mouse bone marrow. J Immunol Methods. 1999;223(1):77–92.

    Article  CAS  PubMed  Google Scholar 

  24. den Haan JMM, Kraal G, Bevan MJ. Cutting edge: lipopolysaccharide induces IL-10-producing regulatory CD4(+) T cells that suppress the CD8(+) T cell response. J Immunol. 2007;178(9):5429–33.

    Article  Google Scholar 

  25. Wu HX, Chen JY, Song SS, Yuan PF, Liu LH, Zhang YF, et al. Beta2-adrenoceptor signaling reduction in dendritic cells is involved in the inflammatory response in adjuvant-induced arthritic rats. Sci Rep. 2016:6.

  26. Xiao RP, Avdonin P, Zhou YY, Chen HP, Akhter SA, Eschenhagen T, et al. Coupling of beta(2)-adrenoceptor to G(i) proteins and its physiological relevance in murine cardiac myocytes. Circ Res. 1999;84(1):43–52.

    Article  CAS  PubMed  Google Scholar 

  27. Banquet S, Delannoy E, Agouni A, Dessy C, Lacomme S, Hubert F, et al. Role of G(i/o)-Src kinase-PI3K/Akt pathway and caveolin-1 in beta(2)-adrenoceptor coupling to endothelial NO synthase in mouse pulmonary artery. Cell Signal. 2011;23(7):1136–43.

    Article  CAS  PubMed  Google Scholar 

  28. Daaka Y, Luttrell LM, Lefkowitz RJ. Switching of the coupling of the beta(2)-adrenergic receptor to different G proteins by protein kinase a. Nature. 1997;390(6655):88–91.

    Article  CAS  PubMed  Google Scholar 

  29. Kolmus K, Tavernier J, Gerlo S. Beta(2)-adrenergic receptors in immunity and inflammation: stressing NF-kappa B. Brain Behav Immun. 2015;45:297–310.

    Article  CAS  PubMed  Google Scholar 

  30. Wang Y, De Arcangelis V, Gao X, Ramani B, Jung YS, Xiang Y. Norepinephrine-and epinephrine-induced distinct beta(2)-adrenoceptor signaling is dictated by GRK2 phosphorylation in cardiomyocytes. J Biol Chem. 2008;283(4):1799–807.

    Article  CAS  PubMed  Google Scholar 

  31. Roche PA, Furuta K. The ins and outs of MHC class II-mediated antigen processing and presentation. Nat Rev Immunol. 2015;15(4):203–16.

    Article  CAS  PubMed  Google Scholar 

  32. Casals C, Barrachina M, Serra M, Lloberas J, Celada A. Lipopolysaccharide up-regulates MHC class II expression on dendritic cells through an AP-1 enhancer without affecting the levels of C11TA. J Immunol. 2007;178(10):6307–15.

    Article  CAS  PubMed  Google Scholar 

  33. Lee KW, Lee Y, Kim DS, Kwon HJ. Direct role of NF-kappa B activation in Toll-like receptor-triggered HLA-DRA expression. Eur J Immunol. 2006;36(5):1254–66.

    Article  CAS  PubMed  Google Scholar 

  34. Ueshima H, Inada T, Shingu K. Suppression of phagosome proteolysis and Matrigel migration with the alpha(2)-adrenergic receptor agonist dexmedetomidine in murine dendritic cells. Immunopharmacol Immunotoxicol. 2013;35(5):558–66.

    Article  CAS  PubMed  Google Scholar 

  35. Sanders VM. The beta2-adrenergic receptor on T and B lymphocytes: do we understand it yet? Brain Behav Immun. 2012;26(2):195–200.

    Article  CAS  PubMed  Google Scholar 

  36. Roncarolo MG, Bacchetta R, Bordignon C, Narula S, Levings MK. Type 1 T regulatory cells. Immunol Rev. 2001;182:68–79.

    Article  CAS  PubMed  Google Scholar 

  37. Belizario JE, Brandao W, Rossato C, Peron JP. Thymic and postthymic regulation of naive CD4(+) T-cell lineage fates in humans and mice models. Mediat Inflamm 2016.

Download references

Acknowledgements

We would like to thank Brian Kobilka and Michel Barrot for their kind gift of β2-AR KO mice. We are grateful to Béatrice Blanchet and Florent Poirier for animal care.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Author information

Authors and Affiliations

  1. IECM, Oniris, INRA, Université Bretagne Loire, Nantes, France

    Julie Hervé, Karine Haurogné, Elodie Bacou, Sylvie Pogu, Marie Allard, Grégoire Mignot, Jean-Marie Bach & Blandine Lieubeau

Authors
  1. Julie Hervé
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Karine Haurogné
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Elodie Bacou
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Sylvie Pogu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Marie Allard
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Grégoire Mignot
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jean-Marie Bach
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Blandine Lieubeau
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Julie Hervé or Blandine Lieubeau.

Ethics declarations

Ethical approval

All applicable international and national guidelines for the care and use of animals were followed. All procedures performed in studies involving mice were in accordance with the ethical standards of the institution at which the studies were conducted.

Conflict of interest

The authors declare that they have no conflicts of interest.

Electronic supplementary material

Supplemental Figure 1

Salbutamol effect on cytokine production by CD4+ T cells is not observed when cocultured with β2-AR−/− DCs. OT-II CD4+ T cells were co-cultured with β2-AR−/− bmDCs pre-incubated with OVA323–339 peptide +/− LPS and salbutamol. At day 3, supernatants were collected and tested for cytokine secretion. (GIF 39 kb)

High resolution image (TIFF 262 kb)

Supplemental Figure 2

Salbutamol does not affect IL-6 and IFNγ production after vaccination. β2-AR+/+ mice were vaccinated with OVA protein in the presence of LPS and treated with vehicle or salbutamol. Spleen cells were harvested 7 days later and restimulated in vitro with OVA protein. Four days after, supernatants were collected and assayed for IL-6 and IFNγ concentrations. In each graph, results are expressed relatively to the mean of the vehicle-treated group. Each symbol represents one mouse and pooled data from two independent experiments are shown. (GIF 20 kb)

High resolution image (TIFF 189 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Hervé, J., Haurogné, K., Bacou, E. et al. β2-adrenergic stimulation of dendritic cells favors IL-10 secretion by CD4+ T cells. Immunol Res 65, 1156–1163 (2017). https://doi.org/10.1007/s12026-017-8966-3

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12026-017-8966-3

Keywords

Search

Navigation