Perforin deficiency and susceptibility to cancer

Abstract

Cytotoxic lymphocytes (CLs) are the killer cells that destroy intracellular pathogen-infected and transformed cells, predominantly through the cytotoxic granule-mediated death pathway. Soluble cytotoxic granule components, including pore-forming perforin and pro-apoptotic serine proteases, granzymes, synergize to induce unscheduled apoptosis of the target cell. A complete loss of CL function results in an aggressive immunoregulatory disorder, familial hemophagocytic lymphohistiocytosis, whereas a partial loss of function seems to be a factor strongly predisposing to hematological malignancies. This review discusses the pathological manifestations of CL deficiencies due to impaired perforin function and describes novel aspects of perforin biology. Cell Death and Differentiation (2010) 17, 607-615; doi:10.1038/cdd.2009; published online 15 January 2010Cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells, collectively called cytotoxic lymphocytes (CLs), kill virusinfected and transformed cells through a number of contactdependent mechanisms. 1,2 Engagement of death receptors by membrane-bound members of the TNF superfamily of death ligands is critical for maintaining lymphoid homeostasis in the host. By contrast, studies of gene deficiencies indicate that defects of the granule exocytosis pathway result in a failure to eliminate infected cells or those that pose a risk of subsequent malignancy. Although cytotoxic granules contain diverse toxins that together contribute to apoptosis induction, this review will deal exclusively with the critical role of the pore-forming protein perforin (PRF) as an essential enabler of target-cell apoptosis, and its more recently described role as a potential 'extrinsic' tumor suppressor.Perforin is a 67-kDa pore-forming protein that is stored and released from the secretory granules (SGs) of CLs along with a number of pro-apoptotic serine protease granzymes that display broad substrate specificities. 3 Following exocytic release, PRF and the granzymes are exposed to the neutral pH and calciumrich environment of the immune synapse. 4 After binding calcium through their C2 domains, PRF monomers acquire the ability to bind generic lipids in the target cell membrane, 5 and then coalesce into large transmembrane pores that permit the granzymes to access key death substrates in the cytosol. [6][7][8] Although the diverse apoptotic pathways triggered by granzymes have been extensively studied and are now understood in considerable detail, it is only of late that insights into the molecular and cellular functions of PRF have been even partly addressed.In this review, we will re-examine the pathological consequences of PRF deficiency, both in mice and humans. In doing so, important differences in PRF biology between these species will be described. We will discuss the pathogenic effect of a number of recently described missense mutations of human PRF. In particular, although the complete absence of PRF function typically results in an aggressive, fatal immunoregulatory disorder of ea...

Altered CD94/NKG2A and perforin expression reduce the cytotoxic activity in malignant pleural effusions

“…28 Additionally, perforin deficiency increases the susceptibility to cancer. 13 Indeed, these concepts are consistent with our present findings, in that CD8+ CTL and NK cells from malignant PF have elevated intracellular expression of CD94/NKG2A (i.e. activated form of receptor), undetectable perforin expression and a reduced ability to lyse tumour target cells.…”

“…Perforin forms pores in the plasma membrane of target cell allowing granzymes types of serine proteases, to enter the target cell, which then activates a series of enzymes, the caspase cascade that eventually lead to apoptosis. 13 Human NK cells are generally recognised as sentinels of the innate immune system due to their inherent capacity to deal with diseased (stressed) cells, including malignant cells. 14 More than 90% of circulating NK cells express moderate levels of CD56 (CD56dim NK cells) and high levels of CD16 and are heterogeneous in the expression of CD94 and NKG2A molecules.…”

Perforin gene mutations in 77 Chinese patients with lymphomas

“…[15,16,17] Perforin mutations resulting in the decrease or absence of the protein or its activity cause the uncontrolled cellular proliferation or lymphoproliferative disorders. [7,18] EBV infection is closely correlated to lymphoma in some cases.…”

Granzymes in disease: bench to bedside

“…Indeed, as discussed by Brennan et al, 6 a complete loss of cytotoxic lymphocyte perforin function results in familial haemophagocytic lymphohistiocytosis, while a partial loss of perforin function appears to strongly predispose patients to haematological malignancies. However, although perforin knockout mice are susceptible to tumorigenesis, the same cannot be said for single granzyme knockout mice, suggesting that it is necessary to prevent the internalization of multiple granzymes and/or other factors to attenuate tumour clearance.…”