Perforin and granzymes: function, dysfunction and human pathology

Abstract

A defining property of cytotoxic lymphocytes is their expression and regulated secretion of potent toxins, including the pore-forming protein perforin and serine protease granzymes. Until recently, mechanisms of pore formation and granzyme transfer into the target cell were poorly understood, but advances in structural and cellular biology have now begun to unravel how synergy between perforin and granzymes brings about target cell death. These and other advances are demonstrating the surprisingly broad pathophysiological roles of the perforin–granzyme pathway, and this has important implications for understanding immune homeostasis and for developing immunotherapies for cancer and other diseases. In particular, we are beginning to define and understand a range of human diseases that are associated with a failure to deliver active perforin to target cells. In this Review, we discuss the current understanding of the structural, cellular and clinical aspects of perforin and granzyme biology.

Influenza virus A(H1N1)2009 antibody-dependent cellular cytotoxicity in young children prior to the H1N1 pandemic

“…4). In addition to the release of NK-mediated IFN-g in the original protocol to measure NK cell activity, we also measured the release of perforin from NK cells, which is elementary for the killing of infected target cells (Voskoboinik et al, 2015). Overall, we showed that the sera containing a PA titre against HA1 A(H1N1) induced an increase in % IFNg/CD107A-positive NK cells ( Fig.…”

Gene Expression Profiling of Bronchoalveolar Lavage Cells Preceding a Clinical Diagnosis of Chronic Lung Allograft Dysfunction

“…We also find increased expression of transcripts encoding key regulators of cytotoxic cells including regulator of G Protein Signaling-1 (RGS1), eomesodermin (EOMES), B-cell CLL/lymphoma 11B (zinc finger protein), synuclein, alpha (SNCA), and T cell receptor beta constant 1 (TRBC1), all of which are involved in different aspects of differentiation and proliferation/clonal expansion of effector memory cells [33][34][35][36][37]. Finally, both CD8 + T cells and NK cells have conserved pathways that mediate target allograft cell injury via perforin, granzymes and granulysin, each of which is differentially over-expressed in incipient CLAD cases [38]. It is also of interest that multiple genes related to hemoglobin (HB) expression are increased in the BAL CP from cases of incipient CLAD.…”

Sinonasal T-Cell Expression of Cytotoxic Mediators Granzyme B and Perforin is Reduced in Patients with Chronic Rhinosinusitis

“…Granzyme B (GrB) is a serine protease that regulates inflammation, apoptosis, and antiviral immunity. 2,3 As such, GrB has also been shown to be a marker of a cell's cytotoxic capacity. 4 The entry of GrB into a cell is facilitated by the pore-forming protein, perforin.…”