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 Th y-1 surface proteins. While the TCR-triggered signaling initiates both perf orin- and Fas ligand (FasL)-Fas-mediated mechanisms of cytotoxicity, it was not clear which mechanism was utilized by Thy-1-triggered signals and whic h pathway of cytotoxicity was triggered at low levels of antigen expression . It is shown that glycophosphatidylinositol-linked surface glycoprotein Th y-1 preferentially activates FasL-Fas- but not perforin-mediated cytotoxici ty. This is explained by the lesser intensity of Thy-1-mediated signaling i n T cells. The data suggest that Thy-1-triggered Fas-mediated cytotoxicity is completely dependent on cross-talk between Thy-1 and Ton signals since m utations in TCR-CD3 complex molecules or inhibition of tyrosine kinases or calcineurin abolished or strongly inhibited Thy-1-triggered FasL-Fas-mediat ed cytotoxicity. Lower concentrations of antigenic peptide or levels of cro ss-linking with anti-TCR-CDS mAb are required to trigger Fas-mediated than perforin-mediated cytotoxicity by different cytotoxic T lymphocyte (CTL) li nes and clones, and it is shown that cross-linking of Thy-1 is much less ef ficient in triggering accumulation of second messengers (intracellular Ca2) 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 rece ptor.