Activation-Induced T Cell Death: Resistance or Susceptibility Correlate with Cell Surface Fas Ligand Expression and T Helper Phenotype

Activated T cells undergo apoptosis when the Fas-antigen (Apo-1, CD95) is ligated by Fas ligand molecules (FasL) or agonistic anti-Fas antibodies. Restimulation of T lymphocytes via the TCR/CD3 complex induces activation-induced cell death (AICD). AICD and Fas-induced cell death are causally related since TCR-induced AICD at least in part depends on Fas/FasL interactions. Thus, restimulation of T cells leads to FasL gene transcription and surface expression. Membrane-bound or secreted FasL molecules then bind to Fas receptors on the same cell or on a neighbor cell to trigger the death signaling cascade. We have compared Fas-mediated apoptosis and AICD in a panel of human T cell clones. While all clones were killed by anti-Fas mAb, several clones were resistant to AICD triggered by anti-TCR/CD3 mAb or superantigen. The pattern of TCR-induced protein tyrosine phosphorylation was comparable in AICD-resistant and -susceptible clones, as was the induction of FasL mRNA. However, significant differences were observed at the level of FasL surface expression which was induced in AICD-susceptible but not in AICD-resistant clones. Cytokine profiles of CD3-stimulated clone cells support the recent observations that AICD sensitivity is restricted to the Th1 subset. However, AICD-resistance is not only associated with the classical Th2 phenotype.