CD4+ T-CELL-MEDIATED KILLING OF MAJOR HISTOCOMPATIBILITY COMPLEX CLASS-II-POSITIVE ANTIGEN-PRESENTING CELLS (APC) .3. CD4+ CYTOTOXIC T-CELLS INDUCE APOPTOSIS OF APC

A subset of CD4+ T cells, belonging to the T helper type 1 (T(h)1) cells, kills antigen-presenting cells (APC) in an antigen-specific and major histocompatibility complex (MHC) class II-restricted way. Evidence is presented that CD4+ cytotoxic T lymphocytes (CTL) induce apoptosis or programmed cell death within susceptible APC as witnessed by quantitative DNA fragmentation. Apoptosis is more reliable to determine cell death than the Cr-51-release assay, because some cells demonstrate resistance to CD4-mediated lysis in the Cr-51-release assay. Apoptosis becomes manifest after 2 to 4 h of incubation preceding the disintegration of the target cells which is detectable between 12 and 24 h as measured by the Cr-51-release assay. Unstimulated B cells, which are not killed, but function as APC, do not undergo apoptosis, whereas lipopolysaccharide or anti-mu-activated B cell blasts show apoptosis and are efficiently lysed. Several CD4+ T(h)2-type cells tested, which did not demonstrate killing of APC as measured by the Cr-51-release assay, are unable to mediate programmed cell death of appropriate APC. Actinomycin D or cycloheximide, inhibitors of transcription and translation, respectively, fail to prevent apoptosis of APC excluding the involvement of newly synthesized soluble products as mediators of killing. Pretreatment of CD4+ CTL, but not of APC with 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid, a specific inhibitor of the anion transport, efficiently prevents apoptosis of APC, although the secretion of interleukins is not affected. We propose, that upon contact of the CD4+ CTL with APC, molecules of yet undefined nature are activated and released in a polar fashion at the contact site and induce the endogenous pathway of programmed cell death.