Skip to main content
SpringerLink
Log in

Immunomodulatory function of Treg-derived exosomes is impaired in patients with relapsing-remitting multiple sclerosis

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

Abstract

Multiple sclerosis (MS) is an autoimmune disease which is characterized by neuroaxonal degeneration in the central nervous system. Impaired function of regulatory T cells (Tregs) is believed to be an underlying pathogenic mechanism in MS. Tregs is able to release exosomes, which contain a considerable amount of protein and RNA. Exosomes are capable of transporting their content to other cells where the released content exerts biological functions. Here, we investigated whether Tregs exosomes of RRMS patients or healthy controls might regulate the proliferation or survival of T lymphocytes. Regulatory T cells derived from MS patients or healthy controls were cultured for 3 days and exosomes were purified from supernatants. Treg-derived exosomes were co-cultured with conventional T cells (Tconv). The percentages of Tconv proliferation and apoptosis were measured. Our findings showed that the percentage of proliferation suppression induced by exosomes in patients compared to healthy controls was 8.04 ± 1.17 and 12.5 ± 1.22, respectively, p value = 0.035. Moreover, the rate of Tconv apoptosis induced by exosome of MS patient was less than healthy controls (0.68 ± 0.12 vs. 1.29 ± 0.13; p value = 0.015). Overall, Treg-derived exosomes from MS patients and healthy controls suppressed the proliferation and induced apoptosis in Tconv. However, the effect of MS-derived exosomes was significantly less than healthy controls. Our results point to an alternative Treg inhibitory mechanism which might be important in immunopathogenesis of MS. Although, the cause of the exosomal defect in MS patients is unclear, manipulation of patients’ Treg-derived exosomes to restore their suppressive activity might be considered as a potential therapeutic approach.

ᅟ

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

Similar content being viewed by others

References

  1. Frischer JM, Bramow S, Dal-Bianco A, Lucchinetti CF, Rauschka H, Schmidbauer M, et al. The relation between inflammation and neurodegeneration in multiple sclerosis brains. Brain. 2009;132(5):1175–89.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Geurts JJ, Barkhof F. Grey matter pathology in multiple sclerosis. Lancet Neurol. 2008;7(9):841–51.

    Article  PubMed  Google Scholar 

  3. Ghabaee M, Bayati A, Saroukolaei SA, Sahraian MA, Sanaati MH, Karimi P, et al. Analysis of HLA DR2&DQ6 (DRB1* 1501, DQA1* 0102, DQB1* 0602) haplotypes in Iranian patients with multiple sclerosis. Cell Mol Neurobiol. 2009;29(1):109–14.

    Article  PubMed  CAS  Google Scholar 

  4. Harris VK, Sadiq SA. Biomarkers of therapeutic response in multiple sclerosis: current status. Molecular Diagnosis & Therapy. 2014;18(6):605–17. https://doi.org/10.1007/s40291-014-0117-0.

    Article  CAS  Google Scholar 

  5. Lassmann H, van Horssen J, Mahad D. Progressive multiple sclerosis: pathology and pathogenesis. Nat Rev Neurol. 2012;8(11):647–56.

    Article  PubMed  CAS  Google Scholar 

  6. Popescu BFG, Lucchinetti CF. Pathology of demyelinating diseases. Annual Review of Pathology: Mechanisms of Disease. 2012;7:185–217.

    Article  CAS  Google Scholar 

  7. Salehi Z, Doosti R, Beheshti M, Janzamin E, Sahraian MA, Izad M. Differential frequency of CD8+ T cell subsets in multiple sclerosis patients with various clinical patterns. PLoS One. 2016;11(7):e0159565.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  8. Tzartos JS, Friese MA, Craner MJ, Palace J, Newcombe J, Esiri MM, et al. Interleukin-17 production in central nervous system-infiltrating T cells and glial cells is associated with active disease in multiple sclerosis. Am J Pathol. 2008;172(1):146–55.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  9. Frisullo G, Nociti V, Iorio R, Patanella AK, Marti A, Caggiula M, et al. IL17 and IFNγ production by peripheral blood mononuclear cells from clinically isolated syndrome to secondary progressive multiple sclerosis. Cytokine. 2008;44(1):22–5.

    Article  PubMed  CAS  Google Scholar 

  10. Viglietta V, Baecher-Allan C, Weiner HL, Hafler DA. Loss of functional suppression by CD4+ CD25+ regulatory T cells in patients with multiple sclerosis. J Exp Med. 2004;199(7):971–9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  11. Kitz A, Singer E, Hafler D. Regulatory T cells: from discovery to autoimmunity. Cold Spring Harbor Perspectives in Medicine. 2018:a029041.

  12. Haas J, Korporal M, Balint B, Fritzsching B, Schwarz A, Wildemann B. Glatiramer acetate improves regulatory T-cell function by expansion of naive CD4+ CD25+ FOXP3+ CD31+ T-cells in patients with multiple sclerosis. J Neuroimmunol. 2009;216(1):113–7.

    Article  PubMed  CAS  Google Scholar 

  13. Namdar A, Nikbin B, Ghabaee M, Bayati A, Izad M. Effect of IFN-beta therapy on the frequency and function of CD4(+)CD25(+) regulatory T cells and Foxp3 gene expression in relapsing-remitting multiple sclerosis (RRMS): a preliminary study. J Neuroimmunol. 2010;218(1–2):120–4. https://doi.org/10.1016/j.jneuroim.2009.10.013.

    Article  PubMed  CAS  Google Scholar 

  14. Shevach EM. Mechanisms of foxp3+ T regulatory cell-mediated suppression. Immunity. 2009;30(5):636–45. https://doi.org/10.1016/j.immuni.2009.04.010.

    Article  PubMed  CAS  Google Scholar 

  15. Azimi M, Aslani S, Mortezagholi S, Salek A, Javan MR, Rezaiemanesh A, et al. Identification, isolation, and functional assay of regulatory T cells. Immunol Investig. 2016;45(7):584–602. https://doi.org/10.1080/08820139.2016.1193869.

    Article  CAS  Google Scholar 

  16. Théry C, Zitvogel L, Amigorena S. Exosomes: composition, biogenesis and function. Nat Rev Immunol. 2002;2(8):569–79.

    Article  PubMed  CAS  Google Scholar 

  17. Bobrie A, Colombo M, Raposo G, Théry C. Exosome secretion: molecular mechanisms and roles in immune responses. Traffic. 2011;12(12):1659–68.

    Article  PubMed  CAS  Google Scholar 

  18. Gutiérrez-Vázquez C, Villarroya-Beltri C, Mittelbrunn M, Sánchez-Madrid F. Transfer of extracellular vesicles during immune cell-cell interactions. Immunol Rev. 2013;251(1):125–42.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  19. Colombo M, Raposo G, Théry C. Biogenesis, secretion, and intercellular interactions of exosomes and other extracellular vesicles. Annu Rev Cell Dev Biol. 2014;30:255–89.

    Article  PubMed  CAS  Google Scholar 

  20. Valadi H, Ekstrom K, Bossios A, Sjostrand M, Lee JJ, Lotvall JO. Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat Cell Biol. 2007;9(6):654–9. https://doi.org/10.1038/ncb1596.

    Article  PubMed  CAS  Google Scholar 

  21. Ekstrom K, Valadi H, Sjostrand M, Malmhall C, Bossios A, Eldh M, et al. Characterization of mRNA and microRNA in human mast cell-derived exosomes and their transfer to other mast cells and blood CD34 progenitor cells. J Extracell Vesicles. 2012;1 https://doi.org/10.3402/jev.v1i0.18389.

  22. Mittelbrunn M, Gutiérrez-Vázquez C, Villarroya-Beltri C, González S, Sánchez-Cabo F, González MÁ, et al. Unidirectional transfer of microRNA-loaded exosomes from T cells to antigen-presenting cells. Nat Commun. 2011;2:282.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  23. Mu C, Zhang X, Wang L, Xu A, Ahmed KA, Pang X, et al. Enhanced suppression of polyclonal CD8+ 25+ regulatory T cells via exosomal arming of antigen-specific peptide/MHC complexes. J Leukoc Biol. 2017;101(5):1221–31.

    Article  PubMed  CAS  Google Scholar 

  24. Smyth LA, Ratnasothy K, Tsang JY, Boardman D, Warley A, Lechler R, et al. CD73 expression on extracellular vesicles derived from CD4+ CD25+ Foxp3+ T cells contributes to their regulatory function. Eur J Immunol. 2013;43(9):2430–40. https://doi.org/10.1002/eji.201242909.

    Article  PubMed  CAS  Google Scholar 

  25. Okoye Isobel S, Coomes Stephanie M, Pelly Victoria S, Czieso S, Papayannopoulos V, Tolmachova T, et al. MicroRNA-containing T-regulatory-cell-derived exosomes suppress pathogenic T helper 1 cells. Immunity. 2014;41(1):89–103. https://doi.org/10.1016/j.immuni.2014.05.019.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  26. Goetzl EJ, Boxer A, Schwartz JB, Abner EL, Petersen RC, Miller BL, et al. Altered lysosomal proteins in neural-derived plasma exosomes in preclinical Alzheimer disease. Neurology. 2015;85(1):40–7.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  27. Manterola L, Guruceaga E, Gallego Perez-Larraya J, Gonzalez-Huarriz M, Jauregui P, Tejada S, et al. A small noncoding RNA signature found in exosomes of GBM patient serum as a diagnostic tool. Neuro-Oncology. 2014;16(4):520–7. https://doi.org/10.1093/neuonc/not218.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  28. Kanninen KM, Bister N, Koistinaho J, Malm T. Exosomes as new diagnostic tools in CNS diseases. Biochim Biophys Acta. 2016;1862(3):403–10. https://doi.org/10.1016/j.bbadis.2015.09.020.

    Article  PubMed  CAS  Google Scholar 

  29. Polman CH, Reingold SC, Banwell B, Clanet M, Cohen JA, Filippi M, et al. Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann Neurol. 2011;69(2):292–302. https://doi.org/10.1002/ana.22366.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Long AE, Tatum M, Mikacenic C, Buckner JH. A novel and rapid method to quantify Treg mediated suppression of CD4 T cells. J Immunol Methods. 2017;449:15–22. https://doi.org/10.1016/j.jim.2017.06.009.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  31. Lu L-F, Boldin MP, Chaudhry A, Lin L-L, Taganov KD, Hanada T, et al. Function of miR-146a in controlling Treg cell-mediated regulation of Th1 responses. Cell. 2010;142(6):914–29. https://doi.org/10.1016/j.cell.2010.08.012.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  32. Jeker LT, Bluestone JA. MicroRNA regulation of T-cell differentiation and function. Immunol Rev. 2013;253(1):65–81. https://doi.org/10.1111/imr.12061.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  33. Jeker LT, Zhou X, Gershberg K, de Kouchkovsky D, Morar MM, Stadthagen G, et al. MicroRNA 10a marks regulatory T cells. PLoS One. 2012;7(5):e36684. https://doi.org/10.1371/journal.pone.0036684.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  34. Yu X, Huang C, Song B, Xiao Y, Fang M, Feng J, et al. CD4+CD25+ regulatory T cells-derived exosomes prolonged kidney allograft survival in a rat model. Cell Immunol. 2013;285(1–2):62–8. https://doi.org/10.1016/j.cellimm.2013.06.010.

    Article  PubMed  CAS  Google Scholar 

  35. Xie Y, Zhang X, Zhao T, Li W, Xiang J. Natural CD8+ 25+ regulatory T cell-secreted exosomes capable of suppressing cytotoxic T lymphocyte-mediated immunity against B16 melanoma. Biochem Biophys Res Commun. 2013;438(1):152–5.

    Article  PubMed  CAS  Google Scholar 

  36. Venken K, Hellings N, Broekmans T, Hensen K, Rummens J-L, Stinissen P. Natural naive CD4+ CD25+ CD127low regulatory T cell (Treg) development and function are disturbed in multiple sclerosis patients: recovery of memory Treg homeostasis during disease progression. J Immunol. 2008;180(9):6411–20.

    Article  PubMed  CAS  Google Scholar 

  37. Venken K, Hellings N, Liblau R, Stinissen P. Disturbed regulatory T cell homeostasis in multiple sclerosis. Trends Mol Med. 2010;16(2):58–68.

    Article  PubMed  CAS  Google Scholar 

  38. Buckner JH. Mechanisms of impaired regulation by CD4(+)CD25(+)FOXP3(+) regulatory T cells in human autoimmune diseases. Nat Rev Immunol. 2010;10(12):849–59. https://doi.org/10.1038/nri2889.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  39. Vignali DA, Collison LW, Workman CJ. How regulatory T cells work. Nat Rev Immunol. 2008;8(7):523–32. https://doi.org/10.1038/nri2343.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  40. Schneider A, Long SA, Cerosaletti K, Ni CT, Samuels P, Kita M, et al. In active relapsing-remitting multiple sclerosis, effector T cell resistance to adaptive Tregs involves IL-6–mediated signaling. Sci Transl Med. 2013;5(170):170ra15.

    Article  PubMed  CAS  Google Scholar 

  41. Bhela S, Kempsell C, Manohar M, Dominguez-Villar M, Griffin R, Bhatt P, et al. Nonapoptotic and extracellular activity of granzyme B mediates resistance to regulatory T cell (Treg) suppression by HLA-DR-CD25hiCD127lo Tregs in multiple sclerosis and in response to IL-6. J Immunol. 2015;194(5):2180–9. https://doi.org/10.4049/jimmunol.1303257.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  42. Verderio C, Muzio L, Turola E, Bergami A, Novellino L, Ruffini F, et al. Myeloid microvesicles are a marker and therapeutic target for neuroinflammation. Ann Neurol. 2012;72(4):610–24. https://doi.org/10.1002/ana.23627.

    Article  PubMed  CAS  Google Scholar 

  43. Kimura K, Hohjoh H, Fukuoka M, Sato W, Oki S, Tomi C, et al. Circulating exosomes suppress the induction of regulatory T cells via let-7i in multiple sclerosis. Nat Commun. 2018;9(1):17. https://doi.org/10.1038/s41467-017-02406-2.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  44. Rivoltini L, Chiodoni C, Squarcina P, Tortoreto M, Villa A, Vergani B, et al. TNF-related apoptosis-inducing ligand (TRAIL)–armed exosomes deliver proapoptotic signals to tumor site. Clin Cancer Res. 2016;22(14):3499–512.

    Article  PubMed  CAS  Google Scholar 

Download references

Funding

This study was supported by Tehran University of Medical Sciences grant No.9403-30-30075. Authors appreciate technical help from technicians at Department of Immunology at Tehran University of Medical Sciences.

Author information

Authors and Affiliations

  1. Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Poorsina St., 16 Azar St., Enghelab Ave., Tehran, Iran

    Maryam Azimi, Farshid Noorbakhsh & Maryam Izad

  2. Department of Neurology, Iranian Center of Neurological Research, Imam Khomeini Hospital, Tehran University of Medical Sciences, Tehran, Iran

    Mojdeh Ghabaee

  3. MS Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran

    Abdorreza Naser Moghadasi & Maryam Izad

Authors
  1. Maryam Azimi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mojdeh Ghabaee
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Abdorreza Naser Moghadasi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Farshid Noorbakhsh
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Maryam Izad
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Maryam Izad.

Ethics declarations

The study was approved by ethics committee of Tehran University of Medical Sciences (IR.TUMS.REC.1394.1551) and written informed consent was obtained from each study subject prior to the study.

Conflict of interest

The authors declare that they have no competing interests.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Azimi, M., Ghabaee, M., Moghadasi, A.N. et al. Immunomodulatory function of Treg-derived exosomes is impaired in patients with relapsing-remitting multiple sclerosis. Immunol Res 66, 513–520 (2018). https://doi.org/10.1007/s12026-018-9008-5

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12026-018-9008-5

Keywords

Search

Navigation