FAS LIGAND-MEDIATED CYTOTOXICITY IS DIRECTLY RESPONSIBLE FOR APOPTOSIS OF NORMAL CD4(-CELLS RESPONDING TO A BACTERIAL SUPERANTIGEN() T)

Exposure of naive CD4(+) T lymphocytes to superantigens such as staphy lococcal enterotoxin B (SEE) induces a strong proliferative response. Prolonged exposure or subsequent restimulation of the responding T cel l population with SEE leads to the apoptotic events of activation-indu ced cell death (AICD). However, T cells derived from either Fas-defici ent lpr or Fas ligand-deficient gld autoimmune mouse strains, fail to undergo AICD under these conditions. Instead, these autoimmune T cells mount a vigorous proliferative response, suggesting a critical role f or Fas/FasL interactions in this form of autoapoptosis. In the current study, we found that SEE-induced AICD was tied to the rapid induction of Fast expression in cells constitutively expressing high levels of Fas. Furthermore, the addition of soluble Fas-IgG fusion protein to th e SEB-restimulated cultures blocked AICD and resulted in a 2 degrees p roliferative response that was comparable in magnitude and kinetics to that of the lpr and gld T cells. The rapid onset of apoptosis in norm al T cells subsequent to restimulation with SEE was in direct contrast to the proliferative response of the initial cultures, even though co mparable levels of Fas and Fast RNA were found in T cells after 1 degr ees and 2 degrees challenge. The clonal expansion of the normal T cell s responding to the initial SEE stimulation was, however, dramatically compromised when the normal cells were cocultured with an MRL-lpr res ponder population; addition of soluble Fas-IgG rescued the normal comp onent of the response. Together, these data demonstrate first, that Fa s/FasL interactions are intimately tied to superantigen-induced AICD, a form of autocrine cell death, and second, that Fast-mediated cytotox icity is responsible for the disappearance of normal CD4(+) T cells in lpr cocultures.