Bone Marrow Transplantation (2019) 54:1562–1574 https://doi.org/10.1038/s41409-019-0462-z ARTICLE T-cell frequencies of CD8 + γδ and CD27 + γδ cells in the stem cell graft predict the outcome after allogeneic hematopoietic cell transplantation Ahmed Gaballa 1 ● Arwen Stikvoort 2 ● Björn Önfelt 3,4 ● Jonas Mattsson 2 ● Mikael Sundin 1,5 ● Emma Watz 1,6 ● Michael Uhlin 1,4,6 Received: 23 August 2018 / Revised: 3 January 2019 / Accepted: 20 January 2019 / Published online: 5 February 2019 © Springer Nature Limited 2019 Abstract The impact of intra-graft T cells on the clinical outcome after allogeneic hematopoietic cell transplantation has been investigated. Most previous studies have focused on the role of αβ cells while γδ cells have received less attention. It has been an open question whether γδ cells are beneficial or not for patient outcome, especially with regards to graft versus host disease. In this study, graft composition of γδ cell subsets was analyzed and correlated to clinical outcome in 105 recipients who underwent allogeneic hematopoietic cell transplantation between 2013 and 2016. We demonstrate for the first time that grafts containing higher T-cell proportions of CD8 + γδ cells were associated with increased cumulative incidence of acute graft versus host disease grade II–III (50% vs 22.6%; P = 0.008). Additionally, graft T-cell frequency of CD27 + γδ cells was inversely correlated with relapse (P = 0.006) and CMV reactivation (P = 0.05). We conclude that clinical outcome after allogeneic hematopoietic cell transplantation is influenced by the proportions of distinct γδ cell subsets in the stem cell graft. We also provide evidence that CD8 + γδ cells are potentially alloreactive and may play a role in acute graft versus host disease. This study illustrates the importance of better understanding of the role of distinct subsets of γδ cells in allogeneic hematopoietic cell transplantation. Introduction Allogeneic hematopoietic cell transplantation (HCT) has offered a cure for a wide range of hematological disorders [1, 2]. Although the outcome of this procedure has improved in the last years, its complications can be devas- tating. In this regard, the role of different donor-derived T-cell subsets on the clinical outcome after allogeneic HCT has been extensively investigated [3–5]. Nevertheless, the impact of γδ cells has not yet been fully described. T cells expressing a T-cell receptor (TCR) formed of γδ rather than αβ subunits are known as γδ cells, and represent 1–10% of circulating T cells [6]. Several subsets of γδ cells have been described based on the variable (V) segment expressed by δ chains, of which Vδ1 and Vδ2 are the main subsets and, hence, the most studied [6, 7]. The role played by γδ cells remains an open question in allogeneic HCT. Several studies reported a beneficial role of γδ cells after HCT [8–11]. Nonetheless, some studies have reported a correlation with unfavorable outcome [12]. One of the most frequently addressed, yet inconsistently answered, question is the relationship between γδ cells and * Ahmed Gaballa ahmed.gaballa@ki.se * Michael Uhlin michael.uhlin@ki.se 1 Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden 2 Department of Oncology and Pathology, Karolinska Institutet, Stockholm, Sweden 3 Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden 4 Department of Applied Physics, Science for Life Laboratory, Royal Institute of Technology, Stockholm, Sweden 5 Section of Paediatric Hematology, Immunology and Hematopoietic Cell Transplantation, Astrid Lindgren Children’s Hospital, Karolinska University Hospital, Stockholm, Sweden 6 Department of Immunology and Transfusion Medicine, Karolinska University Hospital, Stockholm, Sweden Supplementary information The online version of this article (https:// doi.org/10.1038/s41409-019-0462-z) contains supplementary material, which is available to authorized users. 1234567890();,: 1234567890();,: