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Immunology

γδT cells elicited by CMV reactivation after allo-SCT cross-recognize CMV and leukemia

Leukemia volume 27, pages 1328–1338 (2013)Cite this article

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Abstract

Human cytomegalovirus (CMV) infections and relapse of disease remain major problems after allogeneic stem cell transplantation (allo-SCT), in particular in combination with CMV-negative donors or cordblood transplantations. Recent data suggest a paradoxical association between CMV reactivation after allo-SCT and reduced leukemic relapse. Given the potential of Vδ2-negative γδT cells to recognize CMV-infected cells and tumor cells, the molecular biology of distinct γδT-cell subsets expanding during CMV reactivation after allo-SCT was investigated. Vδ2neg γδT-cell expansions after CMV reactivation were observed not only with conventional but also cordblood donors. Expanded γδT cells were capable of recognizing both CMV-infected cells and primary leukemic blasts. CMV and leukemia reactivity were restricted to the same clonal population, whereas other Vδ2neg T cells interact with dendritic cells (DCs). Cloned Vδ1 T-cell receptors (TCRs) mediated leukemia reactivity and DC interactions, but surprisingly not CMV reactivity. Interestingly, CD8αα expression appeared to be a signature of γδT cells after CMV exposure. However, functionally, CD8αα was primarily important in combination with selected leukemia-reactive Vδ1 TCRs, demonstrating for the first time a co-stimulatory role of CD8αα for distinct γδTCRs. Based on these observations, we advocate the exploration of adoptive transfer of unmodified Vδ2neg γδT cells after allo-SCT to tackle CMV reactivation and residual leukemic blasts, as well as application of leukemia-reactive Vδ1 TCR-engineered T cells as alternative therapeutic tools.

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Acknowledgements

We thank the members of the stem cell facility at the UMC Utrecht for technical assistance. We also thank Margreet Brouwer for her expert technical assistance. This work was supported by grants of the ZonMW 43400003, VIDI-ZonMW 917.11.337, LSBR 0902, AICR 10-736 and KWF UU-2010-4669 to JK; DFG Clinical Research Unit 183 and DFG Graduate School 1043 to BP; KWF 2008-4240 to SK; and a FEDER (EU/Région Wallone) grant to DV.

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  1. W Scheper and S van Dorp: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Hematology and Immunology, University Medical Center Utrecht, Utrecht, The Netherlands

    W Scheper, S van Dorp, S Kersting, F Pietersma, S Hol, S Heijhuurs, Z Sebestyen, C Gründer, V Marcu-Malina, D van Baarle & J Kuball

  2. Pediatric Blood and Marrow Transplantation Program, University Medical Center Utrecht, Utrecht, The Netherlands

    C Lindemans

  3. Institute for Medical Immunology, Université Libre de Bruxelles (ULB), Brussels, Belgium

    A Marchant & D Vermijlen

  4. Department of Obstetrics and Gynecology, Hôpital Erasme, Brussels, Belgium

    C Donner

  5. Institute for Virology, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany

    B Plachter

  6. Institute of Pharmacy, Université Libre de Bruxelles (ULB), Brussels, Belgium

    D Vermijlen

  7. Department of Internal Medicine and Infectious Diseases, University Medical Center Utrecht, Utrecht, the Netherlands

    D van Baarle

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  1. W Scheper
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Correspondence to J Kuball.

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Author Contributions

WS, SvD, SK, FP, SHo, SHe, ZS, CL, VM-M, CG, AM, CD, DV, DvB and JK designed, performed and analyzed experiments; JK supervised all experiments; WS, SvD and JK wrote the manuscript; and all authors agreed on the final manuscript.

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Scheper, W., van Dorp, S., Kersting, S. et al. γδT cells elicited by CMV reactivation after allo-SCT cross-recognize CMV and leukemia. Leukemia 27, 1328–1338 (2013). https://doi.org/10.1038/leu.2012.374

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