Natural killer cell-mediated lysis of autologous cells modified by gene therapy

This study investigated the role of natural killer (NK) cells as effectors of an immune response against autologous cells modified by gene therapy. T lymphocytes were transduced with LXSN, a retroviral vector adopted for huma n gene therapy that carries the selectable marker gene neo, and the autolog ous NK response was evaluated. We found that (i) infection with LXSN makes cells susceptible to autologous NK cell-mediated lysis; (ii) expression of the neo gene is responsible for conferring susceptibility to lysis; (iii) l ysis of neo-expressing cells is clonally distributed and mediated only by N K clones that exhibit human histocompatibility leukocyte antigen (HLA)-Bw4 specificity and bear KIR3DL1, a Bw4-specific NK inhibitory receptor; and (i v) the targets are cells from HLA-Bw4(+) individuals. Finally, neo peptides anchoring to the Bw4 allele HLA-B27 interfered with KIR3DL1-mediated recog nition of HLA-B27, i.e., they triggered NK lysis. Moreover, neo gene mutati ons preventing translation of two of the four potentially nonprotective pep tides reduced KIR3DL1(+) NK clone-mediated autologous lysis. Thus, individu als expressing Bw4 alleles possess an NK repertoire with the potential to e liminate autologous cells modified by gene therapy. By demonstrating that N K cells can selectively detect the expression of heterologous genes, these observations provide a general model of the NK cell-mediated control of vir al infections.