Perforin‐Dependent and ‐Independent Pathways of Cytotoxicity Mediated by Lymphocytes

Abstract

There is little doubt at the present time that both perforin-dependent and -independent pathways are important in mediating the cytotoxicity associated with lymphocytes. The cell distribution of perforin, initially thought to include both CTL and NK cells, now must be viewed with caution because all previous biochemical studies on CTL have been conducted with cell lines propagated in long-term cultures in the presence of T cell growth factors (IL-2 and perhaps some still undefined factors). Under these conditions, CTL are known to assume a broader, NK-like specificity in target cell killing and may thus differ significantly from primary CTL generated in the body. Accordingly, perforin does not seem to be present in primary CTL activated directly through mixed lymphocyte reactions. It remains to be shown how primary CTL lyse target cells in vivo. Initial studies conducted in several laboratories have already provided some clues. It now seems that even in cultured, perforin-containing CTL, the perforin pathway is not an obligatory mechanism required for target cell killing. Other pathways, possibly involving TNF/lymphotoxin-like molecules, may play a direct role in this type of cytotoxicity. Other still unidentified factors now also need to be sought, including membrane polypeptides that may develop cytotoxicity directly upon cell contact and binding. Although from the studies reviewed here it is clear now that perforin has a more limited role in cell killing than originally proposed, it is still intriguing that it should share structural and functional homologies with complement proteins, drawing paradoxical analogies between two systems (the cellular and the humoral immune systems) which have evolved to become specialized to carry out separate immunological tasks. The cloning of the genes for perforin and for all the C proteins that comprise the MAC should reveal important information on how these genes originated and then diverged during evolution. The cellular distribution of other granule products, such as serine esterases, also must be viewed with caution. A serine esterase activity was initially thought to be CTL-specific. This information stimulated an intensive research activity in many laboratories that resulted in both the purification of a serine esterase family and the cloning of several serine esterase transcripts. It is becoming clear from recent evidence that this group of enzymes is not truly CTL-specific and therefore would not be expected to develop any function rendered absolutely necessary for cytolysis.(ABSTRACT TRUNCATED AT 400 WORDS)

Downregulation of vascular endothelial growth factor receptors by tumor necrosis factor-alpha in cultured human vascular endothelial cells.

“…Although inhibition of endothelial cell growth and survival may serve as a brake on the inflammatory response during the early stages of endothelial activation, this growth inhibition may contribute to pathophysiologic responses in the later stages of cytokine-mediated diseases. For example, in septic shock, neutrophil-and lymphocyte-mediated endothelial cell injury and loss of monolayer integrity may go unrepaired, which in turn would accelerate vascular leakage and increase leukocyte adhesion to the endothelial surface long after the initial infectious insult had subsided (50,51).…”

Fas and its ligand in a general mechanism of T-cell-mediated cytotoxicity.

“…So far, two models for lymphocytemediated cytotoxicity have been proposed-the granule exocytosis model and the induced suicide model (1)(2)(3)(4). Recently, the effector molecules in the former, such as perforin (4) and granzymes (5), have been identified and it has been confirmed that the perforin-dependent mechanism constitutes one primary pathway of CTL-mediated cytotoxicity by the transfection (6) and gene targeting (Hidefumi Kojima and N.S., unpublished data; ref.…”

Pore‐forming protein in individual cytotoxic T lymphocytes: the effect of senescence provides a probe for understanding the lytic mechanism

“…That the average Pfp content per cell is reduced among effector cell populations exhibiting reduced lytic activity suggests that a critical intracellular level of Pfp may be required to produce potent and efficient lytic effector cells. Thus, cells with reduced Pfp levels, such as MLC-stimulated cells from aged mice, may be less efficient for enabling Pfp polymerization [8] and inducing lysis of target cells, andor for recycling to kill additional target cells.…”