Functional significance of the perforin/granzyme cell death pathway

Trapani, Joseph A.; Smyth, Mark J.

doi:10.1038/nri911

Cited by 1,034 publications

(861 citation statements)

References 125 publications

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“…Once activated naïve CTL undergo a program of proliferation and subsequent acquisition of effector function that includes expression of cytotoxic proteins and the capacity to secrete pro-inflammatory cytokines. A major pathway by which CTL clear virus infection is the targeted exocytosis of granules containing various cytolytic proteins, including the pore-forming protein perforin (pfp), and members of the granzyme (grz) serine protease family, towards the infected cell [1]. Once delivered, pfp and grz act synergistically to initiate programmed cell death by both caspase-dependent and independent pathways [2].…”

Section: Introductionmentioning

confidence: 99%

Granzyme A expression reveals distinct cytolytic CTL subsets following influenza A virus infection

et al. 2009

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CTL mediate anti-viral immunity via targeted exocytosis of cytolytic granules containing perforin and members of the granzyme (grz) serine protease family. Here, we provide the first analysis of grzA protein expression by murine anti-viral CTL. During the progression of influenza A virus infection, CTL expressed two divergent cytolytic phenotypes: grzA À B 1 and grzA 1 B 1 . CTL lacked grzA expression during the initial rounds of antigen-driven division. High levels of grzA were expressed by influenza-specific CTL early post infection (day 6), particularly in tissues associated with the infected respiratory tract (bronchoalveolar lavage, lung). Following resolution of influenza infection, a small population of memory CTL expressed grzA. Interestingly, individual influenza A virus-derived epitopespecific CTL expressed different levels of grzA. The grzA expression hierarchy was determined to be K b PB1 703 5 D b F2 62 5 K b NS2 114 4D b NP 366 5 D b PA 224 and inversely correlated with CTL magnitude. Therefore following influenza infection, a CTL cytolytic hierarchy was established relating to the different profiles of antigen expression and relative immunodominance. Analysis of CTL grzA expression during influenza virus immunity has enabled a more detailed insight into the cytolytic mechanisms of virus elimination.

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Section: Introductionmentioning

confidence: 99%

Granzyme A expression reveals distinct cytolytic CTL subsets following influenza A virus infection

et al. 2009

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“…Perforin polymerizes on the target cell membrane and forms pores allowing entry of granzymes that trigger apoptosis of the target cell by cleaving caspases. 8 Biallelic loss-of-function mutations of the perforin gene (PRF1) have been classically associated with about 30% of cases of familial hemophagocytic lymphohistiocytosis (FLH2), a rare life-threatening immune deficiency that occurs in infants and young adults. 9,10 FLH2 has been classically ascribed to decreased capacity of CTL and NK cells to clear viral infections; viral persistence is thought to cause the lymphoproliferative pattern.…”

Section: Introductionmentioning

confidence: 99%

Variations of the perforin gene in patients with multiple sclerosis

et al. 2008

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Perforin is involved in cell-mediated cytotoxicity and mutations of its gene (PRF1) cause familial hemophagocytic lymphohistiocytosis (FLH2). PRF1 sequencing in 190 patients with multiple sclerosis and 268 controls detected two FLH2-associated variations (A91V, N252S) in both groups and six novel mutations (C999T, G1065A, G1428A, A1620G, G719A, C1069T) in patients. All together, carriers of these variations were more frequent in patients than in controls (phenotype frequency: 17 vs 9%, P ¼ 0.0166; odds ratio (OR) ¼ 2.06, 95% confidence interval (CI): 1.13-3.77). Although A91V was the most frequent variation and displayed a trend of association with multiple sclerosis (MS) in the first population of patients and controls (frequency of the 91V allele: 0.076 vs 0.043, P ¼ 0.044), we used it as a marker to confirm PRF1 involvement in MS and assessed its frequency in a second population of 966 patients and 1520 controls. Frequency of the 91V allele was significantly higher in patients than in controls also in the second population (0.075 vs 0.058%, P ¼ 0.019). In the combined cohorts of 1156 patients and 1788 controls, presence of the 91V allele in single or double dose conferred an OR ¼ 1.38 (95% CI ¼ 1.10-1.74). These data suggest that A91V and possibly other perforin variations indicate susceptibility to MS.

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“…After specific ligand engagement, cytolytic cells bind to sensitive target cells and rapidly reorganize cell membrane proteins, accumulating actin, talin and lytic granules at the cell-cell contact site (immunological synapse) [2,3]. Serine proteases (granzymes) and membrane-perturbing proteins, perforins (PFN) and granulysins are then released at the immunological synapse to induce target cell death [4,5]. PFN are phospholipid-binding proteins that can damage the membrane of mammalian cells by insertion in the lipid bilayer, resulting in pore formation.…”

Section: Introductionmentioning

confidence: 99%

Expression and role of phosphatidylcholine‐specific phospholipase C in human NK and T lymphocyte subsets

et al. 2006

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We recently reported evidence of phosphatidylcholine-specific phospholipase C (PC-PLC) involvement in NK cell-mediated cytotoxicity and in lytic granule exocytosis. In the present study, different subpopulations of human PBL were investigated in relation to PC-PLC enzyme expression. While a substantial intracellular amount of PC-PLC was detected in all lymphoid subsets, expression of this enzyme on the outer membrane surface reached high levels only in NK cells, was present at low levels in B lymphocytes and in some TCR gamma/delta T cells and was practically absent in CD4 + and CD8 + T lymphocytes. Moreover, in NK cells two different subpopulations were identified, CD56 dim PC-PLC bright and CD56 bright PC-PLC low/-cells, corresponding to distinct subsets with cytolytic and immunoregulatory functions, respectively. Interestingly, the PC-PLC expression level on the NK membrane surface correlated closely with that of the CD16 receptor, suggesting a possible relationship between enzyme externalization and NK cell maturation. In summary, our results suggest that a high PC-PLC expression on the cell membrane surface of PBL is a peculiarity of NK cytolytic cells, in which the enzyme is apparently involved in the ability of this subset to lyse sensitive target cells.

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Functional significance of the perforin/granzyme cell death pathway

Cited by 1,034 publications

References 125 publications

Granzyme A expression reveals distinct cytolytic CTL subsets following influenza A virus infection

Granzyme A expression reveals distinct cytolytic CTL subsets following influenza A virus infection

Variations of the perforin gene in patients with multiple sclerosis

Expression and role of phosphatidylcholine‐specific phospholipase C in human NK and T lymphocyte subsets

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