Antigen-induced cell death of T effector cells in vitro proceeds via the Fas pathway, requires endogenous interferon-γ and is independent of perforin and granzymes

Abstract

Activation of resting T cells usually leads to their proliferation and differentiation into effector cells and a subsequent decline following elimination of the antigen. A situation of excessive antigen density may result in T cell receptor (TCR)-induced deletion of T effector cells, a process termed antigen-induced cell death (AgICD). Previous studies indicate that AgICD of cytotoxic T cells may be induced by either of the two key cytotoxic processes, granule exocytosis, including perforin and granzymes, or the Fas ligand (FasL)/Fas pathway. By using in vitro-polyclonally activated or ex vivo-derived virus-induced T cell populations from mice with mutations or targeted gene defects in one or more components of the two key cytolytic pathways we now show that TCR-induced apoptosis is only impaired in the absence of FasL and/or Fas, but not in the absence of perforin and/or granzymes. Furthermore, antibody-blockage of FasL alone is sufficient to inhibit early T cell death. Inhibition of both, FasL and tumor necrosis factor (TNF-α) is required to abrogate late apoptosis by AgICD. The fact that antibodies to IFN-γ also inhibit AgICD suggests that the perforin plus granzyme-independent and FaSL and/or TNF-α facilitated process of AgICD of T effector cells is tightly regulated by endogenous IFN-γ.