Selective expansion of human natural killer cells leads to enhanced alloreactivity.
In allogeneic stem cell transplantation (SCT), natural killer (NK) cells lacking their cognate inhibitory ligand can induce graft-versus-leukemia responses, without the induction of severe graft-versus-host disease (GVHD). This feature can be exploited for cellular immunotherapy. In this study, we examined selective expansion of NK cell subsets expressing distinct killer immunoglobulin-like receptors (KIRs) within the whole human peripheral blood NK cell population, in the presence of HLA-Cw3 (C1) or Cw4 (C2) transfected K562 stimulator cells. Coculture of KIR(+) NK cells with C1 or C2 positive K562 cells, in the presence of IL-2+IL-15, triggered the outgrowth of NK cells that missed their cognate ligand. This resulted in an increased frequency of alloreactive KIR(+) NK cells within the whole NK cell population. Also, after preculture with K562 cells lacking their cognate ligand, we observed that this alloreactive NK population revealed higher numbers of CD107(+) cells when cocultured with the relevant K562 HLA-C transfected target cells, as compared to coculture with untransfected K562 cells. This enhanced reactivity was confirmed using primary leukemic cells as target. This study demonstrates that HLA class I expression can mediate the skewing of the NK cell repertoire and enrich the population for cells with enhanced alloreactivity towards leukemic target cells. This feature may support future clinical applications of NK cell-based immunotherapy.
Department of Laboratory Medicine-Laboratory of Medical Immunology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
Diana N
DN
Eissens
Department of Laboratory Medicine-Laboratory of Medical Immunology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
Clive M
CM
Michelo
Department of Laboratory Medicine-Laboratory of Hematology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
Frank W M B
FW
Preijers
Department of Laboratory Medicine-Laboratory of Medical Immunology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
Bram
B
van Cranenbroek
Department of Laboratory Medicine-Laboratory of Medical Immunology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
Kjeld
K
van Houwelingen
Department of Laboratory Medicine-Laboratory of Medical Immunology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
Arnold
A
van der Meer
Department of Laboratory Medicine-Laboratory of Medical Immunology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
Irma
I
Joosten
D049109:Cell Proliferation; D018920:Coculture Techniques; D020544:Graft vs Leukemia Effect / Q000235:genetics / Q000276:immunology; D015236:HLA-C Antigens / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007167:Immunotherapy / Q000379:methods* / Q000639:trends; D019409:Interleukin-15 / Q000276:immunology; D007376:Interleukin-2 / Q000276:immunology; D020014:K562 Cells; D007694:Killer Cells, Natural / Q000276:immunology*; D007938:Leukemia / Q000276:immunology* / Q000628:therapy*; D052118:Lysosomal-Associated Membrane Protein 1 / Q000378:metabolism; D033581:Stem Cell Transplantation; D019076:Transgenes / Q000235:genetics; D014184:Transplantation, Homologous
D015236:HLA-C Antigens; C038653:HLA-C*03 antigen; C039966:HLA-C*04 antigen; D019409:Interleukin-15; D007376:Interleukin-2; D052118:Lysosomal-Associated Membrane Protein 1