title: Identification and characterization of the specific murine NK cell subset supporting graft-versus-leukemia- and reducing graft-versus-host-effects.
abstract: Clinical studies investigating the impact of natural killer (NK) cells in allogeneic hematopoietic stem cell transplantation settings have yielded promising results. However, NK cells are a functionally and phenotypically heterogeneous population. Therefore, we addressed the functional relevance of specific NK cell subsets distinguished by expression of CD117, CD27 and CD11b surface markers in graft-versus-leukemia (GVL)-reaction and graft-versus-host-disease (GVHD). Our results clearly demonstrate that the subset of c-Kit-CD27-CD11b+NK cells expressed multiple cytotoxic pathway genes and provided optimal graft-versus-leukemia-effects, while significantly reducing T cell proliferation induced by allogeneic dendritic cells. Furthermore, these NK cells migrated to inflamed intestinal tissues where graft-versus-host-colitis was efficiently mitigated. For the first time, we identified the c-Kit-CD27-CD11b+NK cell population as the specific effector NK cell subset capable of significantly diminishing GVHD in fully mismatched bone marrow transplantation settings. In conclusion, the subset of c-Kit-CD27-CD11b+NK cells not only supports GVL, but also plays a unique role in the protection against GVHD by migrating to the peripheral GVHD target organs where they exert efficient immunoregulatory activities. These new insights demonstrate the importance of selecting the optimal NK cell subset for cellular immunotherapy following allogeneic hematopoietic stem cell transplantation.
authors.affiliation: Department of Internal Medicine 5; Hematology and Oncology; Friedrich-Alexander Universität Erlangen-Nürnberg; University Hospital Erlangen ; Erlangen, Germany ; Childrens Hospital; Department of Pediatric Hematology and Oncology; Johann Wolfgang Goethe University ; Frankfurt, Germany ; LOEWE Center for Cell and Gene Therapy; Johann Wolfgang Goethe University ; Frankfurt, Germany.
authors.forename: Kathrin
authors.initials: K
authors.lastname: Meinhardt
authors.affiliation: Department of Internal Medicine 5; Hematology and Oncology; Friedrich-Alexander Universität Erlangen-Nürnberg; University Hospital Erlangen ; Erlangen, Germany.
authors.forename: Irena
authors.initials: I
authors.lastname: Kroeger
authors.affiliation: Department of Internal Medicine 5; Hematology and Oncology; Friedrich-Alexander Universität Erlangen-Nürnberg; University Hospital Erlangen ; Erlangen, Germany ; Childrens Hospital; Department of Pediatric Hematology and Oncology; Johann Wolfgang Goethe University ; Frankfurt, Germany ; LOEWE Center for Cell and Gene Therapy; Johann Wolfgang Goethe University ; Frankfurt, Germany.
authors.forename: Ruth
authors.initials: R
authors.lastname: Bauer
authors.affiliation: Department of Internal Medicine 5; Hematology and Oncology; Friedrich-Alexander Universität Erlangen-Nürnberg; University Hospital Erlangen ; Erlangen, Germany ; Childrens Hospital; Department of Pediatric Hematology and Oncology; Johann Wolfgang Goethe University ; Frankfurt, Germany ; LOEWE Center for Cell and Gene Therapy; Johann Wolfgang Goethe University ; Frankfurt, Germany.
authors.forename: Franziska
authors.initials: F
authors.lastname: Ganss
authors.affiliation: Childrens Hospital; Department of Pediatric Hematology and Oncology; Johann Wolfgang Goethe University ; Frankfurt, Germany ; LOEWE Center for Cell and Gene Therapy; Johann Wolfgang Goethe University ; Frankfurt, Germany.
authors.forename: Ilja
authors.initials: I
authors.lastname: Ovsiy
authors.affiliation: Department of Internal Medicine 5; Hematology and Oncology; Friedrich-Alexander Universität Erlangen-Nürnberg; University Hospital Erlangen ; Erlangen, Germany ; Childrens Hospital; Department of Pediatric Hematology and Oncology; Johann Wolfgang Goethe University ; Frankfurt, Germany ; LOEWE Center for Cell and Gene Therapy; Johann Wolfgang Goethe University ; Frankfurt, Germany.
authors.forename: Johanna
authors.initials: J
authors.lastname: Rothamer
authors.affiliation: Department of Nephropathology; Friedrich-Alexander Universität Erlangen-Nürnberg; University Hospital Erlangen ; Erlangen, Germany.
authors.forename: Maike
authors.initials: M
authors.lastname: Büttner
authors.affiliation: Department of Internal Medicine 1; Friedrich-Alexander Universität Erlangen-Nürnberg; University Hospital Erlangen ; Erlangen, Germany.
authors.forename: Imke
authors.initials: I
authors.lastname: Atreya
authors.affiliation: Department of Internal Medicine 1; Friedrich-Alexander Universität Erlangen-Nürnberg; University Hospital Erlangen ; Erlangen, Germany.
authors.forename: Maximilian
authors.initials: M
authors.lastname: Waldner
authors.affiliation: Department of Internal Medicine 5; Hematology and Oncology; Friedrich-Alexander Universität Erlangen-Nürnberg; University Hospital Erlangen ; Erlangen, Germany.
authors.forename: Max
authors.initials: M
authors.lastname: Bittrich
authors.affiliation: Department of Dermatology; Laboratory of Dendritic Cell Biology; Friedrich-Alexander Universität Erlangen-Nürnberg; University Hospital Erlangen ; Erlangen, Germany.
authors.forename: Christian Hk
authors.initials: CH
authors.lastname: Lehmann
authors.affiliation: LOEWE Center for Cell and Gene Therapy; Johann Wolfgang Goethe University ; Frankfurt, Germany ; Department of Hematology/Oncology; Johann Wolfgang Goethe University ; Frankfurt, Germany.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Rieger
authors.affiliation: IZKF Research Group for Experimental Stem Cell Transplantation; Department of Medicine II; University Hospital ; Würzburg, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Beilhack
authors.affiliation: Division of Hematology and Oncology; Department of Medicine; Freiburg University Medical Center; Albert-Ludwigs-University ; Freiburg, Germany.
authors.forename: Robert
authors.initials: R
authors.lastname: Zeiser
authors.affiliation: Department of Internal Medicine 3; University Hospital Regensburg ; Regensburg; Germany ; Regensburg Center for Interventional Immunology (RCI); University Regensburg ; Regensburg, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Edinger
authors.affiliation: Department of Dermatology; Laboratory of Dendritic Cell Biology; Friedrich-Alexander Universität Erlangen-Nürnberg; University Hospital Erlangen ; Erlangen, Germany.
authors.forename: Diana
authors.initials: D
authors.lastname: Dudziak
authors.affiliation: Department of Internal Medicine 5; Hematology and Oncology; Friedrich-Alexander Universität Erlangen-Nürnberg; University Hospital Erlangen ; Erlangen, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Mackensen
authors.affiliation: Department of Internal Medicine 3; University Hospital Regensburg ; Regensburg; Germany ; Regensburg Center for Interventional Immunology (RCI); University Regensburg ; Regensburg, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Rehli
authors.affiliation: Department of Internal Medicine 5; Hematology and Oncology; Friedrich-Alexander Universität Erlangen-Nürnberg; University Hospital Erlangen ; Erlangen, Germany ; Childrens Hospital; Department of Pediatric Hematology and Oncology; Johann Wolfgang Goethe University ; Frankfurt, Germany ; LOEWE Center for Cell and Gene Therapy; Johann Wolfgang Goethe University ; Frankfurt, Germany.
authors.forename: Evelyn
authors.initials: E
authors.lastname: Ullrich
keywords: BMT, bone marrow transplantation; CD11b+ NK = c-Kit−CD27−CD11b+ NK cells; CD27+ NK = c-Kit−CD27+CD11b− NK cells; DP = c-Kit−CD27+CD11b+ NK cells; GVHD; GVHD, graft-versus-host disease; GVL; GVL, graft-versus-leukemia; HSCT, hematopoietic stem cell transplantation; KIR, killer cell immunoglobulin-like receptor; MLR, mixed lymphocyte reaction; NK cells; NK, natural killer; TBI, total body irradiation; c-Kit+ NK = c-Kit+CD27+CD11b− NK cells; stem cell transplantation; tumor immunology