Comparison of Fas- versus perforin-mediated pathways of cytotoxicity in TCR- and Thy-1-activated murine T cells.
T cell-mediated cytotoxicity can be triggered by cross-linking of TCR or Thy-1 surface proteins. While the TCR-triggered signaling initiates both perforin- and Fas ligand (FasL)-Fas-mediated mechanisms of cytotoxicity, it was not clear which mechanism was utilized by Thy-1-triggered signals and which pathway of cytotoxicity was triggered at low levels of antigen expression. It is shown that glycophosphatidylinositol-linked surface glycoprotein Thy-1 preferentially activates FasL-Fas- but not perforin-mediated cytotoxicity. This is explained by the lesser intensity of Thy-1-mediated signaling in T cells. The data suggest that Thy-1-triggered Fas-mediated cytotoxicity is completely dependent on cross-talk between Thy-1 and TCR signals since mutations in TCR-CD3 complex molecules or inhibition of tyrosine kinases or calcineurin abolished or strongly inhibited Thy-1-triggered FasL-Fas-mediated cytotoxicity. Lower concentrations of antigenic peptide or levels of cross-linking with anti-TCR-CD3 mAb are required to trigger Fas-mediated than perforin-mediated cytotoxicity by different cytotoxic T lymphocyte (CTL) lines and clones, and it is shown that cross-linking of Thy-1 is much less efficient in triggering accumulation of second messengers (intracellular Ca(2+)) than cross-linking of TCR on CTL. Taken together, these data reflect the possibility of differential activation of FasL and/or perforin pathways of cytotoxicity depending on the nature of activating stimuli and surface receptor.
Kojima
H
H
Biochemistry and Immunopharmacology Section, Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Building 10/llN3ll, 10 Center Drive, MSC 1892, Bethesda, MD 20892-1892, USA.
Toda
M
M
Sitkovsky
M V
MV
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D019703:Calcineurin / Q000502:physiology; D020013:Calcium Signaling; D016572:Cyclosporine / Q000494:pharmacology; D003602:Cytotoxicity, Immunologic / Q000276:immunology*; D005089:Exocytosis; D053222:Fas Ligand Protein; D017261:Glycosylphosphatidylinositols / Q000032:analysis; D008562:Membrane Glycoproteins / Q000276:immunology*; D051379:Mice; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins; D017260:Receptor-CD3 Complex, Antigen, T-Cell / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D018800:Thy-1 Antigens / Q000276:immunology*; D019014:fas Receptor / Q000276:immunology*
D000911:Antibodies, Monoclonal; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D017261:Glycosylphosphatidylinositols; D008562:Membrane Glycoproteins; D052899:Pore Forming Cytotoxic Proteins; D017260:Receptor-CD3 Complex, Antigen, T-Cell; D018800:Thy-1 Antigens; D019014:fas Receptor; D054353:Perforin; D016572:Cyclosporine; D019703:Calcineurin