Immobilized MHC class I chain-related protein A synergizes with IL-15 and soluble 4-1BB ligand to expand NK cells with high cytotoxicity ex vivo.
Major histocompatibility complex (MHC) class I chain-related protein A (MICA), which is a ligand for human NKG2D, is expressed by a variety of epithelial tumor cells and promotes the activation of natural killer (NK), CD8(+) and γδ-T cells. Although ectopic expression of MICA on tumor cells elicits anti-tumor responses, soluble MICA downregulates the activities of lymphocytes. In this study, we showed that recombinant, immobilized MICA (iMICA) molecules coated on plastic wells weakly promote peripheral NK cell activation, secretion of interferon (IFN)-γ and degranulation without inducing apoptosis. In addition, iMICA synergized with IL-15 and soluble 4-1BB ligand (s4-1BBL) to expand NK cells 25- to 42-fold in a 13-day culture, whereas NK cells stimulated only with IL-15 and s4-1BBL expanded 10- to 16-fold. In contrast to NK cells expanded by IL-15 and s4-1BBL stimulation, NK cells expanded long term in the presence of iMICA exhibited increased cytotoxicity against leukemia cells. These results suggest that large numbers of NK cells with high cytotoxicity can be generated by stimulation with IL-15 and s4-1BBL in the presence of iMICA and that these cells can be used for adoptive cancer immunotherapy.
Gong
Weijuan
W
Department of Immunology, School of Medicine, Yangzhou University, Yangzhou, PR China. wjgong@yzu.edu.cn
Xiao
Weiming
W
Qian
Li
L
Gong
Chunxiang
C
Hu
Maozhi
M
Pan
Xianyuan
X
Ji
Mingchun
M
D053330:4-1BB Ligand / Q000276:immunology* / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D019002:CD56 Antigen / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D005434:Flow Cytometry; D015395:Histocompatibility Antigens Class I / Q000276:immunology* / Q000494:pharmacology; D006801:Humans; D055767:Immobilized Proteins / Q000276:immunology* / Q000494:pharmacology; D019409:Interleukin-15 / Q000276:immunology* / Q000494:pharmacology; D007694:Killer Cells, Natural / Q000166:cytology* / Q000187:drug effects / Q000276:immunology*; D008213:Lymphocyte Activation / Q000187:drug effects; D010641:Phenotype; D017452:Receptors, IgG / Q000378:metabolism; D055607:Receptors, Natural Killer Cell / Q000378:metabolism; D012995:Solubility / Q000187:drug effects
D053330:4-1BB Ligand; D019002:CD56 Antigen; D015395:Histocompatibility Antigens Class I; D055767:Immobilized Proteins; D019409:Interleukin-15; C099187:MHC class I-related chain A; D017452:Receptors, IgG; D055607:Receptors, Natural Killer Cell