Factors regulating the cytotoxic activity of the human natural killer cell line, NK-92.
NK-92, a highly cytotoxic, interleukin-2 (IL-2)-dependent human natural killer (NK) cell line, has been of interest for basic and translational research. We report on a comprehensive analysis of NK-92 for factors implicated in NK cytotoxicity to elucidate factors underlying NK-92's high cytolytic activity and target range. Thus, we hope to develop a method to identify patients best suited to NK-92 immunotherapy. In addition, as a model system, we hope to increase understanding of the basis for the elevated activity exhibited by activated NK (ANK) cells. NK-92 exhibits an unusual receptor expression profile, expressing a relatively large number of activating (NKp30, NKp46, 2B4, NKGD, E, CD28) receptors. Conversely, it expresses few inhibitory receptors (NKGA/B, low levels of KIR2DL4, ILT-2), lacking most of the killer inhibitory receptors (KIRs) clonally expressed on normal NK cells. In addition, NK-92 expresses high levels of molecules involved in the perforin-granzyme cytolytic pathway as well as additional cytotoxic effector molecules including tumor necrosis factor (TNF)-superfamily members FasL, TRAIL, TWEAK, TNF-alpha, indicating the ability to kill via alternative mechanisms. NK-92 also expresses other molecules implicated immune effector cell regulation (CD80, CD86, CD40L, TRANCE) whose relevance in NK killing is unclear. This study provides initial data to develop a method to identify NK-92 susceptible cells (cells expressing ligands for NK-92 activating receptors ie CD48 for 2B4 and CD80/86 for CD28). Furthermore, this work suggests mechanisms that may contribute to ANK cell activity, including modulation of receptor expression to favor activation, up-regulation of cytotoxic effector molecules, and acquisition of new cytolytic pathways.
Maki
G
G
Section of Bone Marrow Transplant and Cell Therapy, Rush Presbyterian-St. Luke's Medical Center, Rush Medical School, Rush University Chicago, IL 60612, USA.
Klingemann
H G
HG
Martinson
J A
JA
Tam
Y K
YK
D015815:Cell Adhesion Molecules / Q000502:physiology; D002460:Cell Line; D003602:Cytotoxicity, Immunologic / Q000502:physiology*; D006801:Humans; D016130:Immunophenotyping; D007694:Killer Cells, Natural / Q000276:immunology*; D037102:Lectins; D008228:Lymphoma, Non-Hodgkin / Q000473:pathology; D005810:Multigene Family; D011971:Receptors, Immunologic / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology
D015815:Cell Adhesion Molecules; D037102:Lectins; D011971:Receptors, Immunologic; D014409:Tumor Necrosis Factor-alpha