The role of T cell receptors in non-MHC-restricted cytotoxicity

Abstract

The relationship between natural killer cells (NK) and cells of the T lineage has been obscured by the existence of poorly characterized clones of presumed NK origin. We have analyzed nine of these cloned cell lines displaying varying levels of cytotoxic activity against NKS YAC-1 target cells for rearrangement and expression of the genes encoding the alpha, beta, and gamma chains of the T cell receptor for antigen. Rearrangements at both the TcR beta and gamma loci were detected in all clones often at both alleles. Rearrangement patterns at the TcR beta locus were identical in several clones, despite different degrees of cytotoxicity. T cell receptor alpha, beta, and gamma genes were expressed as full length transcripts in all clones regardless of their levels of cytotoxic activity. To explore the involvement of cell surface molecules in the cytolytic events, studies were undertaken to determine whether cytotoxic activity could be inhibited by antibodies against CD3, LFA-I, and H-2KdDd. In two selected clones, both alpha and beta chains of the LFA-I molecule were expressed but only monoclonal antibodies against the alpha chain significantly blocked cytotoxicity. Cytotoxicity was also inhibited by monoclonal antibodies against epitopes of H-2KdDd and CD3, the extent of inhibition correlating with the level of surface expression on both clones. These data suggest that conventional alpha/beta heterodimers may be necessary but not sufficient for target cell recognition by these clones. Since T cell receptor rearrangement and expression occur normally in the T cell lineage but not the NK lineage, these results also indicate that a subpopulation of cells with non-MHC-restricted killer activity lies on the T cell differentiation pathway and is selected by in vitro growth with IL-2. The limited rearrangement pattern observed can be explained if only a small subpopulation of T cells is capable of non-MHC-restricted killing, and if certain rearrangements favor self-MHC recognition which is known to block cytolysis in the NK system.