Gamma/delta T cell clones and natural killer cell clones mediate distinct patterns of non-major histocompatibility complex-restricted cytolysis (original) (raw)
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The role of T cell receptors in non-MHC-restricted cytotoxicity
Cellular Immunology, 1989
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 NK' YAC-1 target cells for rearrangement and expression of the genes encoding the (Y, p, and y chains of the T cell receptor for antigen. Rearrangements at both the TcR ,!? and y loci were detected in all clones often at both alleles. Rearrangement patterns at the TcR B locus were identical in several clones, despite different degrees of cytotoxicity. T cell receptor (Y, & and y 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 (Y and p chains of the LFA-I molecule were expressed but only monoclonal antibodies against the (Y 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 (Y/B 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.
Journal of Cellular Biochemistry, 1982
We have investigated the role of target cell major histocompatibility complex antigens (MHC-Ag) in nonspecific lectin-dependent lymphocyte-mediated cytolysis (LDCC). In contrast to previous reports, we provide evidence that in LDCC the lectin Concanavalin A (Con A) does not mediate lysis by simply bridging cytotoxic T lymphocytes (CTL) and targets via cell surface sugars or by activating the lytic function of CTLs attached to targets via the lectin. Lysis occurs when target cells are pretreated with lectin, but not when CTL are pretreated. Moreover, when CTL populations are used as both aggressors and targets, and only one is pretreated with lectin, lysis occurs only in the direction of the pretreated CTL target. We have observed that in LDCC, as in specific CTL-mediated killing, target recognition proceeds through interaction of CTL receptors (distinct from sugar moieties) and target cell surface determinants perhaps modified by, but distinct from, the lectin itself. We present evidence that the target determinants recognized in LDCC are MHC-Ag: 1) Cells that display reduced amounts of MHC-Ag are poor targets in LDCC; 2) removal of MHC-Ag by papain renders targets refractory to LDCC, however susceptibility is regained upon regeneration of MHC-Ag; and 3) antisera to target cell MHC-Ag block LDCC. The latter finding is also observed in oxidation-dependent CTL-mediated cytotoxicity. Involvement of MHC proteins in both specific and nonspecific CTL-mediated lysis reconciles an apparent fundamental distinction between these two processes and suggests a possible role for MHC proteins in a postrecognition step(s) leading to lysis.
Specificity of Two Subsets of Cytotoxic Human gammadelta T-Cell Clones
Scandinavian Journal of Immunology, 1990
Peripheral blood mononuclear cells were enriched for y6 T cells by immunomagnetic separation, stimulated with cells from an allogeneie donor, and cloned. T-lymphocyte clones (TLC) of the two major 7,5 T-cell subsets. BB3*^ (i.e. V.^2 *) and .^TCSI ' (i.e. V^I/(D)/J.51), were obtained. In addition, one yS TLC was BB3-^TCSl". All of the BB.l"^ TLC showed strong cytotoxicity against various allogeneie lumour cell lines, such as Daudi and K562. The cytotoxicily against the tumour cell lines was modulated by MoAb against the y6 TcR. The BB3' TLC were nol cytotoxic against B-lymphoblastoid cell lines (B-LCL). In contrast, iheiSTCSI ' TLC showed much lower cytotoxic activity against the tumour cell lines, but many were strongly cytotoxic against allogeneie B-LCL. Some of ihc i5TCSI + TLC demonstrated HLA-speeific eytotoxicity. while other (5TCS1 * TLC had a more broad cytolylic activity against B-LCL. Thus, the two major subtypes of y^ T cells from this donor, as defined by MoAb BB3 and (5TCS1, were distinct with respect to recognition specificity.
European Journal of Immunology, 2001
Cytolytic T lymphocytes (CTL) are known to recognize antigen peptides in association with major histocompatibility complex (MHC) class I molecules expressed on target cells. However, a fraction of human CD8 + CTL has been shown to lyse certain natural killer (NK)susceptible target cells via still undefined mechanism(s). These CD8 + T cells, hereafter referred to as NK-CTL, are frequently composed of cells expressing one single TCR V g expansion (different in different individuals), display a memory phenotype and express HLA class I-specific inhibitory NK receptors. Here we show that cell populations or clones of NK-CTL isolated from three healthy donors homogeneously expressed V g 16, V g 9 and V g 3 TCR, respectively. Various clones isolated under limiting dilution conditions from V g 16 + cells of donor 1 displayed identical TCR V g and V § rearrangements, thus suggesting a substantial monoclonality of the NK-CTL subset analyzed. NK-CTL lysed a number of NK-susceptible tumor target cells with the exception of those characterized by g 2-microglobulin ( g 2m) deficiency. However, the latter targets became susceptible to lysis upon g 2m transfection. Using monoclonal antibodies specific for the relevant TCR V g or g 2m we provide evidence suggesting that target cell lysis by NK-CTL is mediated by the TCR itself upon recognition of g 2m-associated proteins. The cellular distribution of the potential g 2m-associated proteins in susceptible target cells suggested, as a likely candidate for TCR-mediated recognition, the non-classical HLA-E molecule. The use, as target cells, of the murine TAP2-deficient RMA-S cells, either untransfected or transfected with HLA-E, and loaded with an appropriate HLA-E-binding peptide, provided the direct demonstration that HLA-E represents a ligand recognized by the TCR expressed by NK-CTL. This is the first evidence that human TCR § / g can recognize HLA-E molecules, thus revealing a novel type of TCR-mediated recognition, which may offer new insight in immune responses in both normal and disease conditions.