Skip to main content
SpringerLink
Log in

Anti-T Lymphocyte Globulin (ATG) Induces Generation of Regulatory T Cells, at Least Part of Them Express Activated CD44

  • Published:
Journal of Clinical Immunology Aims and scope Submit manuscript

Abstract

We show here that the anti-T lymphocyte immunoglobulin (ATG) can induce Treg cells following 24-h incubation in human peripheral blood mononuclear cells (PBMCs). The ATG-induced Treg cells express known cell surface markers (e.g., CD25, FoxP3) and suppress the proliferation of autologous responder PBMCs, stimulated with allogeneic PBMCs, when added into the mixed lymphocyte culture (MLC) at zero time point or 48 h later. We expanded the characteristics of the ATG-induced human Treg cells by showing that they express a novel biomarker designated “activated CD44”. ATG-induced Treg cells retain their suppressor function after freezing and thawing or irradiation. Suppression of MLC by ATG-induced Treg cells is consistently seen when the Treg cells and the responder cells were derived from the same donor, but not when they derived from different donors. Finally, patients undergoing stem cell transplantation and conditioned with ATG generate in vivo Treg cells that suppress MLC.

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
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9

Similar content being viewed by others

References

  1. Mothy M. Mechanism of action of antithymocyte globulin: T cell depletion and beyond. Leukemia. 2007;21:1387–94.

    Article  Google Scholar 

  2. Vignali DA, Collison LW, Workman CJ. How regulatory T cells work. Nat Rev Immunol. 2008;8:523–32.

    Article  PubMed  CAS  Google Scholar 

  3. Lopez M, Clarkson MR, Albin M, Sayegh MH, Najafian N. A novel mechanism of action for anti-thymocyte globulin: induction of CD4+CD25+FoxP3+ regulatory T cells. J Am Soc Nephrol. 2006;17:2844–53.

    Article  PubMed  CAS  Google Scholar 

  4. Feng X, Kajigaya S, Solomou EE, Keyvanfar K, Xu X, Raghavachari N, et al. Rabbit ATG but not horse ATG promotes expansion of functional CD4+CD25highFOXP3+. Blood. 2008;111:3675–83.

    Article  PubMed  CAS  Google Scholar 

  5. Ruzek MC, Waire JS, Hopkins D, Lacorcia G, Sullivan J, Roberts BL, et al. Characterization of in vitro antimurine thymocyte globulin-induced regulatory T cells that inhibit graft-versus-host disease in vivo. Blood. 2008;111:1726–34.

    Article  PubMed  CAS  Google Scholar 

  6. Broady R, Yu J, Levings MK. ATG-induced expression of FOXP3 in human CD4(+) T cells in vitro is associated with T-cell activation and not the induction of FOXP3(+) T regulatory cells. Blood. 2009;114:5003–6.

    Article  PubMed  CAS  Google Scholar 

  7. Vogt Sionov R, Naor D. Hyaluronan-independent lodgement of CD44+ lymphoma cells in lymphoid organs. Int J Cancer. 1997;71:462–9.

    Article  PubMed  CAS  Google Scholar 

  8. Naor D, Vogt Sionov R, Ish-Shalom D. CD44: structure, function and its association with the malignant process. Adv Cancer Res. 1997;71:241–319.

    Article  PubMed  CAS  Google Scholar 

  9. Naor D, Nedvetzki S, Golan I, Faitelson Y. CD44 in cancer. Crit Rev Clin Lab Sci. 2002;39:527–79.

    Article  PubMed  CAS  Google Scholar 

  10. Nedvetzki S, Gonen E, Assayag N, Reich R, Williams RO, Thurmond L, et al. RHAMM, a receptor for hyaluronan-mediated motility compensates for CD44 in inflamed CD44-knockout mice: a different interpretation of redundancy. Proc Natl Acad Sci USA. 2004;101:18081–6.

    Article  PubMed  CAS  Google Scholar 

  11. Pure E, Cuff CA. A crucial role for CD44 in inflammation. Trends Mol Med. 2001;7:213–21.

    Article  PubMed  CAS  Google Scholar 

  12. Firan M, Dhillon S, Estess P, Siegelman MH. Suppressor activity and potency among regulatory T cells is discriminated by functionally active CD44. Blood. 2006;107:619–27.

    Article  PubMed  CAS  Google Scholar 

  13. Bollyky PL, Lord JD, Masewicz SA, Evanko SP, Buckner JH, Wight TN, et al. Cutting edge: high molecular weight hyaluronan promotes the suppressive effects of CD4+CD25+ regulatory T cells. J Immunol. 2007;179:744–7.

    PubMed  CAS  Google Scholar 

  14. Liu T, Soong L, Liu G, König R, Chopra AK. CD44 expression positively correlates with Foxp3 expression and suppressive function of CD4+ Treg cells. Biol Direct. 2009;4:40.

    Article  PubMed  Google Scholar 

  15. Min B, Thornton A, Caucheteux SM, Younes SA, Oh K, Hu-Li J, et al. Gut flora antigens are not important in the maintenance of regulatory T cell heterogeneity and homeostasis. Eur J Immunol. 2007;37:1916–23.

    Article  PubMed  CAS  Google Scholar 

  16. Littman DR, Rudensky AY. Th17 and regulatory T cells in mediating and restraining inflammation. Cell. 2010;140:845–58.

    Article  PubMed  CAS  Google Scholar 

  17. Chung DT, Korn T, Richard J, Ruzek M, Kohm AP, Miller S, et al. Anti-thymocyte globulin (ATG) prevents autoimmune encephalomyelitis by expending myelin antigen-specific FoxPox3+ regulatory T cells. Int Immunol. 2007;19:1003–10.

    Article  PubMed  CAS  Google Scholar 

  18. Korn T, Bettelli E, Oukka M, Kuchroo VK. IL-17 and IL-17 cells. Annu Rev Immunol. 2009;27:485–517.

    Article  PubMed  CAS  Google Scholar 

  19. Kahaly GJ, Shimony O, Gellman YN, Lytton SD, Eshkar-Sebban L, Rosenblum N, et al. Regulatory T-cell in Graves’ orbitopathy: baseline findings and immunomodulation by anti-T lymphocyte globulin. J Clin Endocrinol Metab. 2011;96:422–9.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This research was supported by a non-restricted grant from Fresenius Biotech GmbH, Munich, Germany.

Conflict of interest

The authors declare no conflict of interest.

Author information

Authors and Affiliations

  1. Lautenberg Center for General and Tumor Immunology, The Hebrew University Hadassah Medical School, Jerusalem, 91220, Israel

    Orly Shimony, Yechiel N. Gellman, Efrat Refaeli, Nir Rosenblum, Lora Eshkar-Sebban & David Naor

  2. Department of Hematology and Bone Marrow Transplantation, Chaim Sheba Medical Center, Tel Hashomer, Israel

    Arnon Nagler, Ronit Yerushalmi, Avichai Shimoni & Anfisa Stanevsky

  3. Sera Dialogistics, Munich, Germany

    Simon D. Lytton

  4. Department of Bone Marrow Transplantation, Hadassah University Hospital, Jerusalem, Israel

    Reuven Or

Authors
  1. Orly Shimony
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Arnon Nagler
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yechiel N. Gellman
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Efrat Refaeli
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Nir Rosenblum
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Lora Eshkar-Sebban
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Ronit Yerushalmi
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Avichai Shimoni
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Simon D. Lytton
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Anfisa Stanevsky
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Reuven Or
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. David Naor
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to David Naor.

Additional information

Orly Shimony and Arnon Nagler equally contributed for the project described in this manuscript.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Shimony, O., Nagler, A., Gellman, Y.N. et al. Anti-T Lymphocyte Globulin (ATG) Induces Generation of Regulatory T Cells, at Least Part of Them Express Activated CD44. J Clin Immunol 32, 173–188 (2012). https://doi.org/10.1007/s10875-011-9599-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10875-011-9599-2

Keywords

Search

Navigation