Hematopoietic stem cell transplantation (HSCT) is often the only curative treatment for a wide variety of hematologic malignancies. Donor selection in these diseases is crucial, given that transplanted cells can mediate not only the desired graft-versus-leukemia effect but also graft-versus-host disease (GVHD). Here, we demonstrate that in the absence of NKp46, a major killer receptor expressed by human and mouse natural killer (NK) cells, GVHD is greatly exacerbated, resulting in rapid mortality of the transplanted animals because of infection with commensal bacteria. Furthermore, we demonstrate that the exacerbated GVHD is the result of an altered ability of immune cells to respond to stimulation byimmature dendritic cells. Because high and low expression of NKp46 on NK cells is observed in different individuals, our data indicate that choosing NKp46-high donors for the treatment of different hematologic malignancies might lead to better tumor eradication while minimizing GVHD.
Bibliographical noteFunding Information:
The research leading to these results has received funding from the European Research Council (ERC) under the European Union’s Seventh Framework Program (FP/2007-2013)/ERC grant agreement number 320473-BacNK. Additional support came from the GIF foundation, the Lewis Family Foundation, the ICRF professorship grant, the Israeli Science Foundation, and the European Consortium (MRTN-CT-2005 and LSCH-CT-2005-518178). O.M. is a Crown professor of molecular immunology. H.G. was supported by the Marie Curie Research Training Network program MRTN-CT-2005-019248. H.G. is currently employed by MedImmune Limited, Cambridge, UK. However, the work described here was performed before employment with MedImmune commenced, and MedImmune had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.