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

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 (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-mu-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'-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.

Macrophage Apoptosis in the Central Nervous System in Experimental Autoimmune Encephalomyelitis

“…In EAE, encephalitogenic T cells might kill macrophages that have ingested myelin debris. Cytotoxic T-cell activity directed against antigen-presenting cells plays an important role in the down-regulation of the immune response and in the prevention of tissue damage by hyperactivated macrophages [17]. Thirdly, the toxic products of activated macrophages themselves may be responsible for the macrophage apoptosis.…”

Studies of the mechanism of cytolysis by tumour-infiltrating lymphocytes

“…CD4 þ cells of the Th2 subset have little killing potential [45][46][47][48]. A few studies have pointed out, however, that CD4 þ cells may also lyse targets via a Ca 2þ -dependent mechanism [49][50][51]. Importantly, it has been demonstrated that some tumours may be resistant to Fas-mediated killing, by virtue of Bcl-2 expression, but remain susceptible to perforin-mediated lysis [8,10,11] In this study, we have assessed the ability of TIL to mediate tumour destruction by both Ca 2þ -dependent and -independent mechanisms.…”

Eradication of metastatic tumour cells from lymph nodes by local administration of anti-CD3 antibody

“…Though LLC or P815 turnout cells were resistant to soluble TNF, TNFc~-resistant cells were reported to have TNFa receptors and internalize the receptor-ligand complex into the cells [22]. Recently CD4+ T cells were reported to induce apoptosis of macrophages in an antigen-specific way [6]. These findings, together with the observation of blocking of the cytotoxicity with anti-TNFc~, strongly suggest that activated CD4+ T cells induce programmed cell death of tumour cells through signal transduction by membrane-integrated TNF.…”