Killing by cytotoxic T cells and natural killer cells: Multiple granule serine proteases as initiators of DNA fragmentation

Abstract

SummaryThe vectorial secretion of the contents of highly specialized cytoplasmic granules is of pivotal importance to the killing hy cytotoxic T cells and natural killer cells. The purification and biochemical characterization of some of the granule constituents, in particular the pore-forming protein perforin, had engendered the notion that the killing of cellular targets was largely an osmotic phenomenon analogous to the insult delivered by complement attack. However, the apparent absence of membrane perforation in various examples of lymphocyte-mediated killing, and the observation that perforin alone could not account for apoptosis associated witb programmed cell death, suggested that perforin activity represented, at best, only a part of the whole mechanism. More recently, the characterization of a large family of granule serine proteases (granzymes) has provided evidence that these molecules may collaborate in the killing process by inducing a 'suicide' pathway in target cells, resulting in DNA fragmentation. However, the serine proteases are inactive alone, their natural substrates have not been defined and they require access into the target cell cytoplasm via perforin-induced pores to exert their deleterious effects. Thus, we propose that the cytotoxic granule-mediated mechanism comprises at least two interdependent arms, perforin and serine proteases, that together arc capable of inflicting cell death by osmotic shock and/or nuclear collapse.

Adherence of human immunodeficiency virus-infected lymphocytes to fetal placental cells: a model of maternal --> fetal transmission.

“…The transient release of p24 into culture supernatants was probably from viable and dying inoculum cells. Since cytotoxic T lymphocytes are thought to deliver lytic signals by triggering apoptosis in targets (33)(34)(35), our findings may have implications for the ability of HIV-specific cytotoxic T lymphocytes to eliminate intraplacental infected cells. Additionally, HIV-induced apoptosis of infected cells (36) may be inhibited when these cells are in intimate contact with placental tissue, thereby prolonging their period of potential HIV transmission to the fetal circulation.…”

Endothelial Injury in Internal Organs of University of California at Davis Line 200 (UCD 200) Chickens, an Animal Model for Systemic Sclerosis (Scleroderma)

“…Although the mechanism of vascular damage in SSc has long been investigated, it remains unclear. Several factors have been implicated to cause endothelial injury, including granzyme A and B [17][18][19][20], AECA [21,22] complement factors [23] and oxygen free radicals [24]. Recent findings in a study of skin biopsies of UCD 200 chickens and human SSc patients revealed that endothelial cell apoptosis is a primary event in the pathogenesis of SSc, possibly induced by AECA-dependent cellular cytotoxity (ADCC) [25,26].…”

Cell death in vasculitic neuropathy

“…31 For this purpose, the granules of cytotoxic T cells contain numerous proteins, including granzymes, TIA-1, and perforin. Stimuli like IL-2 or the binding of CD28 act via protein tyrosine ki- nases to induce polarization of various cytotoxic Tcell organelles, including the cytolytic granules.…”