Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Manuscript
  • Published:

BMT and Stem Cells

Minor histocompatibility antigen-specific T cells with multiple distinct specificities can be isolated by direct cloning of IFNγ-secreting T cells from patients with relapsed leukemia responding to donor lymphocyte infusion

Leukemia volume 19, pages 83–90 (2005)Cite this article

Abstract

Graft-vs-leukemia reactivity after donor lymphocyte infusion (DLI) can be mediated by donor T cells recognizing minor histocompatibility antigens (mHags) on recipient hematopoietic cells. To study the diversity of cells involved in this immune response, hematopoietic cell reactive T cells were directly clonally isolated from peripheral blood of patients entering complete remission after DLI. T cells were briefly stimulated with bone marrow cells from patients pretransplant, and IFNγ-secreting T cells were directly clonally isolated, and expanded. Cytotoxic T-lymphocyte (CTL) clones from individual patients used multiple distinct HLA-restricting molecules and varied in reactivity against patient-derived normal and/or malignant hematopoietic cells. For each patient, CTL clones specific for known immunodominant mHags as well as distinct unknown mHags were found. Within individual patients, CTL clones using the same HLA-restricting element could show differential recognition patterns, indicating further diversity in mHag reactivity. CTL clones from individual patients exhibiting identical specificities could show oligoclonal origin. In conclusion, the direct cloning technique shows that the response to hematopoietic cells after DLI is directed against multiple distinct mHags, including but not limited to known immunodominant mHags, implying that immunotherapy with T cells against multiple mHag specificities may be more effective in eradicating malignant cells.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3

Similar content being viewed by others

References

  1. Falkenburg JH, van de Corput, Marijt EW, Willemze R . Minor histocompatibility antigens in human stem cell transplantation. Exp Hematol 2003; 31: 743–751.

    Article  CAS  Google Scholar 

  2. Marijt WA, Heemskerk MH, Kloosterboer FM, Goulmy E, Kester MG, Van Der Hoorn MA et al. Hematopoiesis-restricted minor histocompatibility antigens HA-1- or HA- 2-specific T cells can induce complete remissions of relapsed leukemia. Proc Natl Acad Sci USA 2003; 100: 2742–2747.

    Article  CAS  Google Scholar 

  3. Mutis T, Goulmy E . Hematopoietic system-specific antigens as targets for cellular immunotherapy of hematological malignancies. Semin Hematol 2002; 39: 23–31.

    Article  Google Scholar 

  4. Riddell SR, Berger C, Murata M, Randolph S, Warren EH . The graft versus leukemia response after allogeneic hematopoietic stem cell transplantation. Blood Rev 2003; 17: 153–162.

    Article  Google Scholar 

  5. den Haan JM, Meadows LM, Wang W, Pool J, Blokland E, Bishop TL et al. The minor histocompatibility antigen HA-1: a diallelic gene with a single amino acid polymorphism. Science 1998; 279: 1054–1057.

    Article  CAS  Google Scholar 

  6. den Haan JM, Sherman NE, Blokland E, Huczko E, Koning F, Drijfhout JW et al. Identification of a graft versus host disease-associated human minor histocompatibility antigen. Science 1995; 268: 1476–1480.

    Article  CAS  Google Scholar 

  7. Spierings E, Brickner AG, Caldwell JA, Zegveld S, Tatsis N, Blokland E et al. The minor histocompatibility antigen HA-3 arises from differential proteasome-mediated cleavage of the lymphoid blast crisis (Lbc) oncoprotein. Blood 2003; 102: 621–629.

    Article  CAS  Google Scholar 

  8. Brickner AG, Warren EH, Caldwell JA, Akatsuka Y, Golovina TN, Zarling AL et al. The immunogenicity of a new human minor histocompatibility antigen results from differential antigen processing. J Exp Med 2001; 193: 195–206.

    Article  CAS  Google Scholar 

  9. Vogt MH, de Paus RA, Voogt PJ, Willemze R, Falkenburg JH . DFFRY codes for a new human male-specific minor transplantation antigen involved in bone marrow graft rejection. Blood 2000; 95: 1100–1105.

    CAS  PubMed  Google Scholar 

  10. Wang W, Meadows LR, den Haan JM, Sherman NE, Chen Y, Blokland E et al. Human H-Y: a male-specific histocompatibility antigen derived from the SMCY protein. Science 1995; 269: 1588–1590.

    Article  CAS  Google Scholar 

  11. Vogt MH, Goulmy E, Kloosterboer FM, Blokland E, de Paus RA, Willemze R et al. UTY gene codes for an HLA-B60-restricted human male-specific minor histocompatibility antigen involved in stem cell graft rejection: characterization of the critical polymorphic amino acid residues for T-cell recognition. Blood 2000; 96: 3126–3132.

    CAS  PubMed  Google Scholar 

  12. Vogt MH, van den Muijsenberg JW, Goulmy E, Spierings E, Kluck P, Kester MG et al. The DBY gene codes for an HLA-DQ5-restricted human male-specific minor histocompatibility antigen involved in graft-versus-host disease. Blood 2002; 99: 3027–3032.

    Article  CAS  Google Scholar 

  13. Akatsuka Y, Nishida T, Kondo E, Miyazaki M, Taji H, Iida H et al. Identification of a polymorphic gene, BCL2A1, encoding two novel hematopoietic lineage-specific minor histocompatibility antigens. J Exp Med 2003; 197: 1489–1500.

    Article  CAS  Google Scholar 

  14. Nishida T, Akatsuka Y, Morishima Y, Hamajima N, Tsujimura K, Kuzushima K et al. Clinical relevance of a newly identified HLA-A24-restricted minor histocompatibility antigen epitope derived from BCL2A1, ACC-1, in patients receiving HLA genotypically matched unrelated bone marrow transplant. Br J Haematol 2004; 124: 629–635.

    Article  CAS  Google Scholar 

  15. Korngold R, Wettstein PJ . Immunodominance in the graft-vs-host disease T cell response to minor histocompatibility antigens. J Immunol 1990; 145: 4079–4088.

    CAS  PubMed  Google Scholar 

  16. Perreault C, Roy DC, Fortin C . Immunodominant minor histocompatibility antigens: the major ones. Immunol Today 1998; 19: 69–74.

    Article  CAS  Google Scholar 

  17. Wettstein PJ, Bailey DW . Immunodominance in the immune response to ‘multiple’ histocompatibility antigens. Immunogenetics 1982; 16: 47–58.

    Article  CAS  Google Scholar 

  18. Choi EY, Yoshimura Y, Christianson GJ, Sproule TJ, Malarkannan S, Shastri N et al. Quantitative analysis of the immune response to mouse non-MHC transplantation antigens in vivo: the H60 histocompatibility antigen dominates over all others. J Immunol 2001; 166: 4370–4379.

    Article  CAS  Google Scholar 

  19. van Els CA, D'Amaro J, Pool J, Blokland E, Bakker A, van Elsen PJ et al. Immunogenetics of human minor histocompatibility antigens: their polymorphism and immunodominance. Immunogenetics 1992; 35: 161–165.

    Article  CAS  Google Scholar 

  20. Rufer N, Wolpert E, Helg C, Tiercy JM, Gratwohl A, Chapuis B et al. HA-1 and the SMCY-derived peptide FIDSYICQV (H-Y) are immunodominant minor histocompatibility antigens after bone marrow transplantation. Transplantation 1998; 66: 910–916.

    Article  CAS  Google Scholar 

  21. Kloosterboer FM, Luxemburg-Heijs SAP, Soest RA, Barbui AM, Van Egmond HM, Strijbosch MPW et al. Direct cloning of leukemia-reactive T cells from patients treated with donor lymphocyte infusion shows a relative dominance of hematopoiesis-restricted minor histocompatibility antigen HA-1 and HA-2 specific T cells. Leukemia 2004; 18: 798–808.

    Article  CAS  Google Scholar 

  22. Faber LM, Luxemburg-Heijs SA, Veenhof WF, Willemze R, Falkenburg JH . Generation of CD4+ cytotoxic T-lymphocyte clones from a patient with severe graft-versus-host disease after allogeneic bone marrow transplantation: implications for graft-versus-leukemia reactivity. Blood 1995; 86: 2821–2828.

    CAS  PubMed  Google Scholar 

  23. Burrows SR, Kienzle N, Winterhalter A, Bharadwaj M, Altman JD, Brooks A . Peptide-MHC class I tetrameric complexes display exquisite ligand specificity. J Immunol 2000; 165: 6229–6234.

    Article  CAS  Google Scholar 

  24. Arden B, Clark SP, Kabelitz D, Mak TW . Human T-cell receptor variable gene segment families. Immunogenetics 1995; 42: 455–500.

    CAS  PubMed  Google Scholar 

  25. Faber LM, Luxemburg-Heijs SA, Willemze R, Falkenburg JH . Generation of leukemia-reactive cytotoxic T lymphocyte clones from the HLA-identical bone marrow donor of a patient with leukemia. J Exp Med 1992; 176: 1283–1289.

    Article  CAS  Google Scholar 

  26. Smit WM, Rijnbeek M, van Bergen CA, Fibbe WE, Willemze R, Falkenburg JH . T cells recognizing leukemic CD34(+) progenitor cells mediate the antileukemic effect of donor lymphocyte infusions for relapsed chronic myeloid leukemia after allogeneic stem cell transplantation. Proc Natl Acad Sci USA 1998; 95: 10152–10157.

    Article  CAS  Google Scholar 

  27. Van Der Hoorn MA, Luxemburg-Heijs SA, van Bergen CA, Bongaerts R, Willemze R, Falkenburg JH . The progenitor cell inhibition assay to measure the anti-leukemic reactivity of T cell clones against acute and chronic myeloid leukemia. Methods 2003; 31: 113–119.

    Article  CAS  Google Scholar 

  28. Heemskerk MH, de Paus RA, Lurvink EG, Koning F, Mulder A, Willemze R et al. Dual HLA class I and class II restricted recognition of alloreactive T lymphocytes mediated by a single T cell receptor complex. Proc Natl Acad Sci USA 2001; 98: 6806–6811.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The authors would like to thank R van der Linden and M van der Keur for expert technical assistance with the flowcytometric isolation.

Author information

Authors and Affiliations

  1. Department of Hematology, Leiden University Medical Center, Leiden, The Netherlands

    F M Kloosterboer, S A P van Luxemburg-Heijs, R A van Soest, H M van Egmond, M P W Strijbosch, R Willemze & J H F Falkenburg

  2. Hematology Unit, Ospedali Riuniti di Bergamo, Bergamo, Italy

    A M Barbui

Authors
  1. F M Kloosterboer
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. S A P van Luxemburg-Heijs
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. R A van Soest
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. H M van Egmond
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. A M Barbui
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. M P W Strijbosch
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. R Willemze
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. J H F Falkenburg
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to F M Kloosterboer.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kloosterboer, F., van Luxemburg-Heijs, S., van Soest, R. et al. Minor histocompatibility antigen-specific T cells with multiple distinct specificities can be isolated by direct cloning of IFNγ-secreting T cells from patients with relapsed leukemia responding to donor lymphocyte infusion. Leukemia 19, 83–90 (2005). https://doi.org/10.1038/sj.leu.2403572

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.leu.2403572

Keywords

This article is cited by

Search

Advanced search

Quick links