Skip to main content

Advertisement

SpringerLink
Log in

In Vitro Immunological Effects of Blocking CCR5 on T Cells

  • Published:
Inflammation Aims and scope Submit manuscript

Abstract

Blockade of CC chemokine receptor 5 (CCR5) by maraviroc may induce immunological changes independent of its antiviral effects and may have immunoregulation properties. This study was designed to determine the effects of blocking CCR5 on human activated T cells in vitro and investigate the potential immunological mechanisms. Human CD3+ T cells were purified from peripheral blood mononuclear cells and then activated by cytokines. We tested the surface expressions and relative messenger RNA (mRNA) levels of CCR2, CCR5, CCR6, CCR7, and CXCR3, chemotaxis toward their cognate ligands, internalization of chemokine receptors, and production of cytokines. In conclusion, blocking CCR5 by maraviroc not only can block CCR5 and CCR2 internalization processes induced by CCL5 and CCL2, but also inhibit T cell chemotactic activities toward their cognate ligands, respectively. Moreover, blocking CCR5 with maraviroc at high doses tends to decrease the production of TNF-α and IFN-γ. In addition, there might be a form of cross talk between CCR5 and CCR2, and this may offer a novel immunological effect for blockade of CCR5.

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.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

References

  1. Lederman, M.M., A. Penn-Nicholson, M. Cho, and D. Mosier. 2006. Biology of CCR5 and its role in HIV infection and treatment. JAMA 296(7): 815–26.

    Article  CAS  PubMed  Google Scholar 

  2. Alkhatib, G. 2009. The biology of CCR5 and CXCR4. Current Opinion in HIV and AIDS 4(2): 96–103.

    Article  PubMed Central  PubMed  Google Scholar 

  3. Geleff, S., D. Draganovici, P. Jaksch, and S. Segerer. 2010. The role of chemokine receptors in acute lung allograft rejection. The European Respiratory Journal 35(1): 167–75.

    Article  CAS  PubMed  Google Scholar 

  4. Lo, D.J., T.A. Weaver, D.E. Kleiner, R.B. Mannon, L.M. Jacobson, B.N. Becker, et al. 2011. Chemokines and their receptors in human renal allotransplantation. Transplantation 91(1): 70–7.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  5. Palmer, L.A., G.E. Sale, J.I. Balogun, D. Li, D. Jones, J.J. Molldrem, et al. 2010. Chemokine receptor CCR5 mediates allo-immune responses in graft-versus-host disease. Biology of Blood and Marrow Transplantation 16(3): 311–9.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  6. Ukena, S.N., S. Velaga, R. Geffers, J. Grosse, U. Baron, S. Buchholz, et al. 2011. Human regulatory T cells in allogeneic stem cell transplantation. Blood 118(13): e82–92.

    Article  CAS  PubMed  Google Scholar 

  7. Wysocki, C.A., S.B. Burkett, A. Panoskaltsis-Mortari, S.L. Kirby, A.D. Luster, K. McKinnon, et al. 2004. Differential roles for CCR5 expression on donor T cells during graft-versus-host disease based on pretransplant conditioning. The Journal of Immunology 173(2): 845–54.

    Article  CAS  PubMed  Google Scholar 

  8. Murai, M., H. Yoneyama, T. Ezaki, M. Suematsu, Y. Terashima, A. Harada, et al. 2003. Peyer’s patch is the essential site in initiating murine acute and lethal graft-versus-host reaction. Nature Immunology 4(2): 154–60.

    Article  CAS  PubMed  Google Scholar 

  9. Hütter, G., M. Neumann, D. Nowak, S. Klein, H. Klüter, and W.K. Hofmann. 2011. The effect of the CCR5-delta32 deletion on global gene expression considering immune response and inflammation. The Journal of Inflammation (London) 8: 29.

    Article  Google Scholar 

  10. Gilliam, B.L., D.J. Riedel, and R.R. Redfield. 2011. Clinical use of CCR5 inhibitors in HIV and beyond. Journal of Translational Medicine 9(1): S9.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  11. Qiao, S., H. Ren, Y. Shi, and W. Liu. 2014. Allogeneic compact bone-derived mesenchymal stem cell transplantation increases survival of mice exposed to lethal total body irradiation: a potential immunological mechanism. Chinese Medical Journal 127(3): 475–82.

    CAS  PubMed  Google Scholar 

  12. Gulick, R.M., J. Lalezari, J. Goodrich, N. Clumeck, E. DeJesus, A. Horban, et al. 2008. Maraviroc for previously treated patients with R5 HIV-1 infection. The New England Journal of Medicine 359(14): 1429–41.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  13. Boesecke, C., and S.L. Pett. 2012. Clinical studies with chemokine receptor-5 (CCR5)-inhibitors. Current Opinion in HIV and AIDS 7(5): 456–62.

    Article  CAS  PubMed  Google Scholar 

  14. Tan, Q., Y. Zhu, J. Li, Z. Chen, G.W. Han, I. Kufareva, et al. 2013. Structure of the CCR5 chemokine receptor-HIV entry inhibitor maraviroc complex. Science 341(6152): 1387–90.

    Article  CAS  PubMed  Google Scholar 

  15. Arberas, H., and A.C. Guardo. 2013. Bargallo’ ME, Maleno MJ, Calvo M, Blanco JL, et al. In vitro effects of the CCR5 inhibitor maraviroc on human T cell function. The Journal of Antimicrobial Chemotherapy 68(3): 577–86.

    Article  CAS  PubMed  Google Scholar 

  16. Rossi, R., M. Lichtner, A. De Rosa, I. Sauzullo, F. Mengoni, A.P. Massetti, et al. 2011. In vitro effect of anti-human immunodeficiency virus CCR5 antagonist maraviroc on chemotactic activity of monocytes, macrophages and dendritic cells. Clinical and Experimental Immunology 166(2): 184–90.

  17. Reshef, R., S.M. Luger, E.O. Hexner, A.W. Loren, N.V. Frey, S.D. Nasta, et al. 2012. Blockade of lymphocyte chemotaxis in visceral graft-versus-host disease. The New England Journal of Medicine 367(2): 135–45.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  18. Pulido, I., K. Machmach, M.C. Romero-Sanchez, M. Genebat, G. Mendez-Lagares, E. Ruiz-Mateos, et al. 2012. T-cell changes after a short-term exposure to maraviroc in HIV-infected patients are related to antiviral activity. The Journal of Infection 64(4): 417–23.

    Article  PubMed  Google Scholar 

  19. Funderburg, N., M. Kalinowska, J. Eason, J. Goodrich, J. Heera, H. Mayer, et al. 2010. Effects of maraviroc and efavirenz on markers of immune activation and inflammation and associations with CD4+ cell rises in HIV-infected patients. PLoS ONE 5(10): e13188.

    Article  PubMed Central  PubMed  Google Scholar 

  20. Choi, S.W., G.C. Hildebrandt, K.M. Olkiewicz, D.A. Hanauer, M.N. Chaudhary, I.A. Silva, et al. 2007. CCR1/CCL5 (RANTES) receptor-ligand interactions modulate allogeneic T-cell responses and graft-versus-host disease following stem-cell transplantation. Blood 110(9): 3447–55.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  21. O’Boyle, G., J.G. Brain, J.A. Kirby, and S. Ali. 2007. Chemokine-mediated inflammation: Identification of a possible regulatory role for CCR2. Molecular Immunology 44(8): 1944–53.

    Article  PubMed  Google Scholar 

  22. El-Asmar, L., J.Y. Springael, S. Ballet, E.U. Andrieu, G. Vassart, and M. Parmentier. 2005. Evidence for negative binding cooperativity within CCR5-CCR2b heterodimers. Molecular Pharmacology 67(2): 460–9.

    Article  CAS  PubMed  Google Scholar 

  23. Salanga, C.L., M. O’Hayre, and T. Handel. 2009. Modulation of chemokine receptor activity through dimerization and crosstalk. Cellular and Molecular Life Sciences 66(8): 1370–86.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

Download references

Acknowledgments

This study was financially supported by grant from the National Natural Science Foundation of China (No. 81370667).

Conflict of interest

The authors have declared that no competing interests exist.

Author information

Authors and Affiliations

  1. Department of Hematology, Peking University First Hospital, 8 Xishiku Street, Xicheng District, 100034, Beijing, China

    Jing Yuan, Han-yun Ren, Yong-jin Shi & Wei Liu

Authors
  1. Jing Yuan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Han-yun Ren
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yong-jin Shi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Wei Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Han-yun Ren.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Yuan, J., Ren, Hy., Shi, Yj. et al. In Vitro Immunological Effects of Blocking CCR5 on T Cells. Inflammation 38, 902–910 (2015). https://doi.org/10.1007/s10753-014-0052-6

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10753-014-0052-6

KEY WORDS

Search

Navigation