Cytolytic effector mechanisms of human CD4+ cytotoxic T lymphocytes.
To elucidate mechanisms by which human CD4+ cells mediated cytolytic activity, we studied the expression of cytolytic proteins and the effects 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 alpha-p-tosyl-L-lysine chloromethylketone (TLCK), a serine esterase inhibitor, as well as cytochalasin B and monensin, antagonists of secretory pathways, inhibited CD4+ CTLs, whereas the absence of extracellular Ca+2 or the presence of Ca+2 channel blockers partially inhibited cytotoxicity. CD4+ CTLs induced apoptosis of target cell nuclei and membrane 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 cytolysis by CD4+ clones: (1) a Ca+2-dependent mechanism associated with the cytotoxic granules and (2) a Ca+2-insensitive mechanism.
Susskind
B
B
Department of Surgery, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Shornick
M D
MD
Iannotti
M R
MR
Duffy
B
B
Mehrotra
P T
PT
Siegel
J P
JP
Mohanakumar
T
T
D001483:Base Sequence; D015496:CD4-Positive T-Lymphocytes / Q000145:classification* / Q000201:enzymology / Q000276:immunology*; D002118:Calcium / Q000502:physiology; D002467:Cell Nucleus / Q000276:immunology; D002999:Clone Cells; D003601:Cytotoxicity Tests, Immunologic; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D005089:Exocytosis / Q000276:immunology; D005110:Extracellular Space / Q000276:immunology; D006801:Humans; D008969:Molecular Sequence Data; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology
D011500:Protein Synthesis Inhibitors; D002118:Calcium