CYTOLYTIC EFFECTOR MECHANISMS OF HUMAN CD4(-LYMPHOCYTES() CYTOTOXIC T)

To elucidate mechanisms by which human CD4(+) cells mediated cytolytic activity, we studied the expression of cytolytic proteins and the eff ects of inhibitors and mAbs on T-cell clones. Of seven cytolytic CD4() clones, three were specific for the HLA-DR17, while four recognized DR18. Anti-HLA-DR mAb and anti-CD4 mAb blocked lysis. In addition, N-a lpha-p-tosyl-L-lysine chloromethylketone (TLCK), a serine esterase inh ibitor, as well as cytochalasin B and monensin, antagonists of secreto ry pathways, inhibited CD4(+) CTLs, whereas the absence of extracellul ar Ca++ or the presence of Ca++ channel blockers partially inhibited c ytotoxicity. CD4(+) CTLs induced apoptosis of target cell nuclei and m embrane damage simultaneously. The CD4(+) clones synthesized perforin and granzyme B and expressed the granule-associated protein TIA-1. Our studies indicate that two distinct mechanisms may contribute to cytol ysis by CD4(+) clones: (1) a Ca++-dependent mechanism associated with the cytotoxic granules and (2) a Ca++-insensitive mechanism.