CYTOLYTIC T-LYMPHOCYTES DISPLAYING NATURAL-KILLER (NK)-LIKE ACTIVITY - EXPRESSION OF NK-RELATED FUNCTIONAL RECEPTORS FOR HLA CLASS-I MOLECULES (P58 AND CD94) AND INHIBITORY EFFECT ON THE TCR-MEDIATED TARGET-CELL LYSIS OR LYMPHOKINE PRODUCTION

Natural killer (NK) cells express surface receptors for defined groups of HLA class I alleles. The specific interaction between these recept ors and HLA class I molecules expressed on target cells results in inh ibition of NK-mediated target cell lysis. In this report, we analyzed whether similar mechanisms were operating in cytolytic T lymphocytes ( CTLs) capable of lysing NK-sensitive target cells. T cell clones were screened for their ability to lyse K562 target cells. The selected clo nes expressed either gamma delta or alpha beta TCR. The majority of th ese clones failed to lyse the HLA class I+ R8/15375 cell line; however , upon addition of the previously described A6-136 (IgM) or 6A4 F(ab') (2) anti-HLA class I mAbs, target cells were efficiently lysed. Lysis of autologous phytohemagglutinin blasts in the presence of anti-HLA cl ass I mAbs occurred primarily with TCR gamma delta(+) CTLs. Recognitio n of HLA class I molecules on target cells implies the expression of N K-related specific receptors in CTL clones. Indeed, phenotypic analysi s of >300 CTL clones with NK-like activity revealed that 28% expressed p58 molecules (specific for HLA-C alleles) while 30% expressed CD94 m olecules (specific for the Bw6 specificity). these receptor molecules were found to function as inhibitory receptors, as revealed by the eff ect of anti-p58 or anti-CD94 mAbs (of IgG isotype) on the lysis of the Fc gamma R(+) K562 target cells. In addition, while the 221 cell line was susceptible to lysis by CTL clones, 221 cells transfected with Cw 3 were not lysed by GL183(+) (p58) clones, thus providing direct evide nce for the specific protection exerted by given HLA class I alleles. Finally, we show that anti-p58 or anti-CD94 mAbs inhibit the T cell ac tivation induced by anti-TCR mAbs. This inhibitory activity has been d etected both on the TCR-triggered target cell lysis and on cytokine tu mor necrosis factor-alpha production.