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Histocompatibility and Donor Selection Issues

Partial break in tolerance of NKG2A−/LIR-1− single KIR+ NK cells early in the course of HLA-matched, KIR-mismatched hematopoietic cell transplantation

Bone Marrow Transplantation volume 52, pages 1144–1155 (2017)Cite this article

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Abstract

Natural killer (NK) cell subpopulations from 8 HLA-matched but killer cell immunoglobulin-like receptor (KIR)/HLA-ligand-mismatched patient–donor pairs were analyzed in the course of allogeneic hematopoietic stem cell transplantation (HCT). The patients’ post-transplantation NKG2A−/LIR-1− NK cells, which expressed only inhibitory KIRs for which the patient had no HLA class I ligands, showed higher cytotoxic capacity than the NKG2A−/LIR-1− NK cells lacking any inhibitory KIRs that remained tolerant throughout the course of HCT. The NKG2A+ NK cell subpopulations displayed the highest levels of cytotoxic activation, which appeared to be significantly enhanced in comparison with that in allogeneic graft’s donors. LIR-1− NK cells were much more frequent after HCT than LIR-1+ NK cells and LIR-1 expression on NKG2A+ or NKG2A− NK cells was associated with significantly lower cytotoxic activities. Thus NKG2A−/LIR-1− NK cells expressing only HLA-mismatched KIRs show a partial break in tolerance in the first year following HCT. The failure to exclude LIR-1+ cells within the NKG2A− NK cell subset in previous studies could explain the earlier conflicting results. Thus systemic immune activation in patients following HCT augments the GvL effect through both increasing overall NK cell activities and partially breaking tolerance of unlicensed NK cells.

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Acknowledgements

We thank the staff of the bone marrow transplantation clinics, laboratories and Station Löhr for their assistance. We thank the José Carreras Leukämie Stiftung and the DFG for grant support. This work was supported by grants R10/34f and R13/14 from the José Carreras Leukämie Stiftung and SFB 620 Z2 from the DFG.

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Author notes

  1. S Rathmann

    Present address: 10Present address: Clinical Trials Unit, University Medical Center Freiburg, Elsässer Str. 2, Freiburg 79110, Germany.,

  2. S Rathmann and C Keck: These authors contributed equally in this work.

Authors and Affiliations

  1. Department of Pathology, University Medical Center Freiburg, Freiburg, Germany

    S Rathmann, C Keck, M Müller, S Glatzel, M Werner & P Fisch

  2. Faculty of Biology, University of Freiburg, Freiburg, Germany

    C Keck

  3. Physics Department and Freiburg Center for Biosystems Analysis (ZBSA), University of Freiburg, Freiburg, Germany

    C Kreutz & J Timmer

  4. Beckman Coulter GmbH, Krefeld, Germany

    N Weit

  5. BIOSS Centre for Biological Signalling Studies, University of Freiburg, Freiburg, Germany

    J Timmer

  6. Department of Hematology/Oncology, University Medical Center Freiburg, Freiburg, Germany

    M Follo & J Finke

  7. Department of Medical Microbiology and Immunology, UW School of Medicine and Public Health, Madison, WI, USA

    M Malkovsky

  8. Children’s University Hospital, Tübingen, Germany

    R Handgretinger

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Rathmann, S., Keck, C., Kreutz, C. et al. Partial break in tolerance of NKG2A−/LIR-1− single KIR+ NK cells early in the course of HLA-matched, KIR-mismatched hematopoietic cell transplantation. Bone Marrow Transplant 52, 1144–1155 (2017). https://doi.org/10.1038/bmt.2017.81

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