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Immunobiology

TCRγδ cytotoxic T lymphocytes expressing the killer cell-inhibitory receptor p58.2 (CD158b) selectively lyse acute myeloid leukemia cells

Bone Marrow Transplantation volume 27, pages 1087–1093 (2001)Cite this article

Abstract

Cytotoxic T lymphocytes (CTL) are thought to play an important role in the graft-versus-leukemia (GVL) response. Unfortunately, GVL reactivity is often associated with life-threatening graft-versus-host disease (GVHD). Characterization of CTL that selectively attack leukemic cells but not normal cells may lead to the development of adjuvant immunotherapy that separates GVL from GVHD. Here, we describe TCRγδ (Vγ9/Vδ1) CTL, isolated from the peripheral blood of an AML patient after stem cell transplantation (SCT), that very efficiently lysed freshly isolated acute myeloid leukemia (AML) cells and AML cell lines. Interestingly, HLA-matched non-malignant hematopoietic cells were not killed. We revealed that the killer cell-inhibitory receptor (KIR) p58.2 (CD158b) specific for group 2 HLA-C molecules negatively regulates the cytotoxic effector function displayed by these TCRγδ CTL. First, an antibody against HLA-C enhances lysis of non-malignant cells. Secondly, stable transfection of HLA-Cw*0304 into the class I-negative cell line 721.221 inhibited lysis. Finally, engagement of p58.2 by antibodies immobilized on FcγR-expressing murine P815 cells inhibits CD3- and TCRγδ-directed lysis. Compared to non-malignant hematopoietic cells, AML cells express much lower levels of MHC class I molecules making them susceptible to lysis by p58.2+ TCRγδ CTL. Such KIR-regulated CTL reactivity may have a role in the GVL response without affecting normal tissues of the host and leading to GVHD. Bone Marrow Transplantation (2001) 27, 1087–1093.

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Acknowledgements

We thank Dr J Melenhorst, Dr A Bakker and Dr P Coulie for generously providing MoAb and Dr V Braud for kindly providing the 721.221 Cw*0304 and Cw*0401 stable transfectants. This work was supported by grants from the Dutch Cancer Society (KUN 97–1508).

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Authors and Affiliations

  1. Department of Hematology, University Medical Center St Radboud, Nijmegen, The Netherlands

    H Dolstra, H Fredrix, T de Witte & E van de Wiel-van Kemenade

  2. Department of Bloodtransfusion and Transplantation Immunology, University Medical Center St Radboud, Nijmegen, The Netherlands

    A van der Meer

  3. Department of Tumor Immunology, University Medical Center St Radboud, Nijmegen, The Netherlands

    C Figdor

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  1. H Dolstra
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Dolstra, H., Fredrix, H., van der Meer, A. et al. TCRγδ cytotoxic T lymphocytes expressing the killer cell-inhibitory receptor p58.2 (CD158b) selectively lyse acute myeloid leukemia cells. Bone Marrow Transplant 27, 1087–1093 (2001). https://doi.org/10.1038/sj.bmt.1703043

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