Skip to main content

Suppressor Properties of Human CD8+CD28− T Cells in Mixed Leukocyte Reaction are not Affected by CsA and RAPA

Archivum Immunologiae et Therapiae Experimentalis volume 64, pages 409–416 (2016)Cite this article

Abstract

Human CD8+CD28− T suppressor cells were previously shown to be involved in the control of the immune response to transplanted allografts. It seems essential to examine how immunosuppressive drugs influence these cells. However, the CD8+CD28− population contains both suppressor (Ts) and cytotoxic (Tc) T cells, and the phenotype of the Ts subpopulation has not been identified explicitly. It is proposed that the transcription factor FOXP3 may be helpful in distinguishing the Ts and Tc subpopulations. The aim of this study was to evaluate the influence of the immunosuppressive drugs cyclosporine A (CsA) and rapamycin (RAPA) on the level, suppressor properties, and phenotype of human CD8+CD28− T cells in vitro. The model used was the mixed leukocyte reaction performed with peripheral blood mononuclear cells from healthy volunteers. It was observed that CD8+CD28− T cells from cultures with CsA or RAPA had similar suppressor properties to cells from control cultures, although the drugs influenced the expression of FOXP3. CsA and RAPA did not interfere with the suppressor properties of human CD8+CD28− T cells in vitro, although they affected the expression of the FOXP3 molecule.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

43,34 €

Price includes VAT (Finland)
Tax calculation will be finalised during checkout.

Fig. 1
Fig. 2

References

  • Abraham RT (1998) Mammalian target of rapamycin: immunosuppressive drugs uncover a novel pathway of cytokine receptor signaling. Curr Opin Immunol 10:330–336

    CAS  Article  PubMed  Google Scholar 

  • Allez M, Brimnes J, Dotan I et al (2002) Expansion of CD8+ T cells with regulatory function after interaction with intestinal epithelial cells. Gastroenterology 123:1516–1526

    Article  PubMed  Google Scholar 

  • Almawi WY, Melemedjian OK (2000) Clinical and mechanistic differences between FK506 (tacrolimus) and cyclosporin A. Nephrol Dial Transplant 15:1916–1918

    CAS  Article  PubMed  Google Scholar 

  • Arosa FA (2002) CD8 + CD28− T cells: certainties and uncertainties of a prevalent human T-cell subset. Immunol Cell Biol 80:1–13

    Article  PubMed  Google Scholar 

  • Arosa FA, Irwin C, Mayer L et al (1998) Interactions between peripheral blood CD8 T lymphocytes and intestinal epithelial cells (iEC). Clin Exp Immunol 112:226–236

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • Assadiasl S, Ahmadpoor P, Nafar M et al (2014) Regulatory T cell subtypes and TGF-β1 gene expression in chronic allograft dysfunction. Iran J Immunol 11:139–152

    PubMed  Google Scholar 

  • Baeten D, Louis S, Braud C et al (2006) Phenotypically and functionally distinct CD8+ lymphocyte populations in long-term drug-free tolerance and chronic rejection in human kidney graft recipients. J Am Soc Nephrol 17:294–304

    CAS  Article  PubMed  Google Scholar 

  • Battaglia M, Stabilini A, Roncarolo MG (2005) Rapamycin selectively expands CD4+ CD25+ FoxP3+ regulatory T cells. Blood 105:4743–4748

    CAS  Article  PubMed  Google Scholar 

  • Bocian K, Borysowski J, Wierzbicki P et al (2010) Rapamycin, unlike cyclosporine A, enhances suppressive functions of in vitro induced CD4+CD25+ Tregs. Nephrol Dial Transplant 25:710–717

    CAS  Article  PubMed  Google Scholar 

  • Calvo-Turrubiartes M, Romano-Moreno S, García-Hernández M et al (2009) Quantitative analysis of regulatory T cells in kidney graft recipients: a relationship with calcineurin inhibitor level. Transpl Immunol 21:43–49

    CAS  Article  PubMed  Google Scholar 

  • Chen BJ, Morris RE, Chao NJ (2000) Graft-versus-host disease prevention by rapamycin: cellular mechanisms. Biol Blood Marrow Transplant 6:529–536

    CAS  Article  PubMed  Google Scholar 

  • Ciubotariu R, Colovai AI, Pennesi G et al (1998) Specific suppression of human CD4+ Th cell responses to pig MHC antigens by CD8+ CD28− regulatory T cells. J Immunol 161:5193–5202

    CAS  PubMed  Google Scholar 

  • Coenen JJ, Koenen HJ, van Rijssen E et al (2006) Rapamycin, and not cyclosporin A, preserves the highly suppressive CD27+ subset of human CD4+ CD25+ regulatory T cells. Blood 107:1018–1023

    CAS  Article  PubMed  Google Scholar 

  • Colovai AI, Ciubotariu R, Liu Z et al (2001) CD8(+)CD28(−) T suppressor cells represent a distinct subset in a heterogeneous population. Transplant Proc 33:104–107

    CAS  Article  PubMed  Google Scholar 

  • Colovai AI, Mirza M, Vlad G et al (2003) Regulatory CD8+ CD28− T cells in heart transplant recipients. Hum Immunol 64:31–37

    CAS  Article  PubMed  Google Scholar 

  • Cortesini R, LeMaoult J, Ciubotariu R et al (2001) CD8+ CD28− T suppressor cells and the induction of antigen-specific, antigen-presenting cell-mediated suppression of Th reactivity. Immunol Rev 182:201–206

    CAS  Article  PubMed  Google Scholar 

  • Effros RB, Dagarag M, Valenzuela HF (2003) In vitro senescence of immune cells. Exp Gerontol 38:1243–1249

    CAS  Article  PubMed  Google Scholar 

  • Furuzawa-Carballeda J, Bostock IC, Lima G et al (2014) Immunophenotyping of peripheral immunoregulatory as well as Th17A and Th22 cell subpopulations in kidney transplant recipients under belatacept or cyclosporine treatment. Transpl Immunol 30:107–113

    CAS  Article  PubMed  Google Scholar 

  • Gao W, Lu Y, El Essawy B et al (2007) Contrasting effects of cyclosporine and rapamycin in de novo generation of alloantigen-specific regulatory T cells. Am J Transplant 7:1722–1732

    CAS  Article  PubMed  Google Scholar 

  • Gavin MA, Torgerson TR, Houston E et al (2006) Single-cell analysis of normal and FOXP3–mutant human T cells: FOXP3 expression without regulatory T cell development. Proc Natl Acad Sci USA 103:6659–6664

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • Hohn H, Julch M, Pilch H et al (2003) Definition of the HLA-A2 restricted peptides recognized by human CD8+ effector T cells by flow-assisted sorting of the CD8+ CD45RA+ CD28− T cell subpopulation. Clin Exp Immunol 131:102–110

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • Hu H, Djuretic I, Sundrud MS et al (2007) Transcriptional partners in regulatory T cells: Foxp3, Runx and NFAT. Trends Immunol 28:329–332

    CAS  Article  PubMed  Google Scholar 

  • Korecka-Polak A, Duszota A, Wierzbicki P et al (2011) Human peripheral blood CD8+ CD28− T cells of renal allograft recipients do not express FOXP3 protein. Transplant Proc 43:2917–2921

    CAS  Article  PubMed  Google Scholar 

  • Li B, Greene MI (2008) Special regulatory T-cell review: FOXP3 biochemistry in regulatory T cells—how diverse signals regulate suppression. Immunology 123:17–19

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • Li Y, Zhao X, Cheng D et al (2008) The presence of Foxp3 expressing T cells within grafts of tolerant human liver transplant recipients. Transplantation 86:1837–1843

    CAS  Article  PubMed  Google Scholar 

  • Liu Z, Tugulea S, Cortesini R et al (1998) Specific suppression of T helper alloreactivity by allo-MHC class I-restricted CD8+ CD28− T cells. Int Immunol 10:775–783

    CAS  Article  PubMed  Google Scholar 

  • Manavalan JS, Kim-Schulze S, Scotto L et al (2004) Alloantigen specific CD8+ CD28− FOXP3+ T suppressor cells induce ILT3+ ILT4+ tolerogenic endothelial cells, inhibiting alloreactivity. Int Immunol 16:1055–1068

    CAS  Article  PubMed  Google Scholar 

  • Mantel PY, Ouaked N, Ruckert B et al (2006) Molecular mechanisms underlying FOXP3 induction in human T cells. J Immunol 176:3593–3602

    CAS  Article  PubMed  Google Scholar 

  • Nakamura S, Suzuki M, Sugimoto A et al (2007) IL-2-independent generation of FOXP3(+)CD4(+)CD8(+)CD25(+) cytotoxic regulatory T cell lines from human umbilical cord blood. Exp Hematol 35:287–296

    CAS  Article  PubMed  Google Scholar 

  • Pillai V, Ortega SB, Wang CK et al (2007) Transient regulatory T-cells: a state attained by all activated human T-cells. Clin Immunol 123:18–29

    CAS  Article  PubMed  Google Scholar 

  • Rudensky AY, Gavin M, Zheng Y (2006) FOXP3 and NFAT: partners in tolerance. Cell 126:253–256

    CAS  Article  PubMed  Google Scholar 

  • Scheuring UJ, Sabzevari H, Theofilopoulos AN (2002) Proliferative arrest and cell cycle regulation in CD8(+)CD28(−) versus CD8(+)CD28(+) T cells. Hum Immunol 63:1000–1009

    CAS  Article  PubMed  Google Scholar 

  • Schubert LA, Jeffery E, Zhang Y et al (2001) Scurfin (FOXP3) acts as a repressor of transcription and regulates T cell activation. J Biol Chem 276:37672–37679

    CAS  Article  PubMed  Google Scholar 

  • Scotto L, Naiyer AJ, Galluzzo S et al (2004) Overlap between molecular markers expressed by naturally occurring CD4+ CD25+ regulatory T cells and antigen specific CD4+ CD25+ and CD8+ CD28− T suppressor cells. Hum Immunol 65:1297–1306

    CAS  Article  PubMed  Google Scholar 

  • Segundo DS, Ruiz JC, Izquierdo M et al (2006) Calcineurin inhibitors, but not rapamycin, reduce percentages of CD4+ CD25+ FOXP3+ regulatory T cells in renal transplant recipients. Transplantation 82:550–557

    Article  PubMed  Google Scholar 

  • Strioga M, Pasukoniene V, Characiejus D (2011) CD8+ CD28− and CD8+ CD57+ T cells and their role in health and disease. Immunology 134:17–32

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • Suciu-Foca N, Manavalan JS, Cortesini R (2003) Generation and function of antigen-specific suppressor and regulatory T cells. Transpl Immunol 11:235–244

    CAS  Article  PubMed  Google Scholar 

  • Suciu-Foca N, Manavalan JS, Scotto L et al (2005) Molecular characterization of allospecific T suppressor and tolerogenic dendritic cells: review. Int Immunopharmacol 5:7–11

    CAS  Article  PubMed  Google Scholar 

  • Vlad G, King J, Chang CC et al (2011) Gene profile analysis of CD8(+) ILT3-Fc induced T suppressor cells. Hum Immunol 72:107–114

    CAS  Article  PubMed  Google Scholar 

  • Wang H, Daniel V, Sadeghi M et al (2013) Differences in the induction of induced human CD4+CD25+FoxP3+ T-regulatory cells and CD3+CD8+CD28– T-suppressor cells subset phenotypes in vitro: comparison of phorbol 12-myristate 13-acetate/ionomycin and phytohemagglutinin stimulation. Transplant Proc 45:1822–1831

    CAS  Article  PubMed  Google Scholar 

  • Zavazava N, Kabelitz D (2000) Alloreactivity and apoptosis in graft rejection and transplantation tolerance. J Leukoc Biol 68:167–174

    CAS  PubMed  Google Scholar 

  • Zhou H, Wang ZD, Zhu X et al (2007) CD8 + FOXP3 + T cells from renal transplant recipients in quiescence induce immunoglobulin-like transcripts-3 and -4 on dendritic cells from their respective donors. Transplant Proc 39:3065–3067

    CAS  Article  PubMed  Google Scholar 

  • Zuber J, Viguier M, Lemaitre F et al (2007) Severe FOXP3 + and naive T lymphopenia in a non-IPEX form of autoimmune enteropathy combined with an immunodeficiency. Gastroenterology 132:1694–1704

    CAS  Article  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported in part by grant nos. 3P05B 07,425, N N402 268,036 and N303 015 32/0671 from the Ministry of Science and Higher Education. We thank Anna Duszota and Magdalena Jastrzebska for providing the samples for HLA typing, Marta Zylicz for experimental support regarding the CFSE proliferation assay, Lidia Malchar and Marcin Cichocki for technical assistance, and the Transplantation Institute of the Medical University of Warsaw for kindly providing the immunosuppressive drugs.

Author information

Affiliations

  1. Department of Immunology, Faculty of Biology, University of Warsaw, Miecznikowa 1, 02-096, Warsaw, Poland

    Anna Korecka-Polak, Katarzyna Bocian, Maria Pachówka & Grażyna Korczak-Kowalska

  2. Department of Clinical Immunology, Transplantation Institute, Medical University of Warsaw, Warsaw, Poland

    Agnieszka Jałbrzykowska & Grażyna Korczak-Kowalska

Authors
  1. Anna Korecka-Polak
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Katarzyna Bocian
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Maria Pachówka
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Agnieszka Jałbrzykowska
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Grażyna Korczak-Kowalska
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Grażyna Korczak-Kowalska.

About this article

Verify currency and authenticity via CrossMark

Cite this article

Korecka-Polak, A., Bocian, K., Pachówka, M. et al. Suppressor Properties of Human CD8+CD28− T Cells in Mixed Leukocyte Reaction are not Affected by CsA and RAPA. Arch. Immunol. Ther. Exp. 64, 409–416 (2016). https://doi.org/10.1007/s00005-016-0388-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00005-016-0388-8

Keywords

  • Cyclosporine A
  • CD8+CD28−
  • FOXP3
  • Rapamycin
  • Suppressor T cells