CD4+ T cell‐mediated killing of major histocompatibility complex class II‐positive antigen‐presenting cells (APC) III. CD4+ cytotoxic T cells induce apoptosis of APC

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Abstract
A subset of CD4+ T cells, belonging to the T helper type 1 (Th1) 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 51Cr‐release assay, because some cells demonstrate resistance to CD4‐mediated lysis in the 51Cr‐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 51Cr‐release assay. Unstimulated B cells, which are not killed, but function as APC, do not undergo apoptosis, whereas lipopolysaccharide or anti‐μ‐activated B cell blasts show apoptosis and are efficiently lysed. Several CD4+ Th2‐type cells tested, which did not demonstrate killing of APC as measured by the 51Cr‐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′‐diisothiocyanato‐stilbene‐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.