HUMAN PURIFIED PROTEIN DERIVATIVE-SPECIFIC CD4(-CELLS USE BOTH CD95-DEPENDENT AND CD95-INDEPENDENT CYTOLYTIC MECHANISMS() T)

CTL, both CD4(+) and CD8(+), are essential in the eradication of intra cellular pathogens, Data generated using murine T cells have suggested a critical role for CD95 (Fas, Apo-1) in CD4(+) T cell-induced apopto sis of target cells, In contrast, CD8(+) CTL predominantly use the per forin/granzyme lytic pathway, At present little is known about the mec hanism of CD4(+) CTL lytic function during intracellular infection in humans, We have used human CD4(+) T cells specific for purified protei n derivative (PPD) of Mycobacterium tuberculosis to explore whether CD 95 is the dominant cytolytic mechanism, PPD-reactive CD4(+) clones eff iciently lysed Ag-pulsed autologous monocytes, adherent macrophages, a nd EBV-transformed B cells, Addition of an antagonistic CD95 Ab had a minimal effect on cytolysis, whereas addition of MgEGTA to block perfo rin/granzyme resulted in complete inhibition of killing, In contrast, lysis of activated peripheral blood B cells could be partially blocked with the antagonistic CD95 Ab, Supporting these observations, monocyt es, macrophages, and EBV-transformed B cells were not lysed by an agon istic CD95 Ab, Activated B cells were readily lysed by the agonistic C D95 Ab. T cell clones triggered through tile TCR with anti-CD3 were ca pable of lysing the CD95-sensitive Jurkat T cell line in a CD95-depend ent manner, but were also able to release granzymes, We conclude that human CD4(+) T cells are capable of lysing PPD-pulsed targets using bo th perforin/granzyme and CD95 pathways, The contribution of CD95 is st rictly dependent on target cell susceptibility to CD95-mediated killin g.