Journal ArticleDOI
Perforin-mediated target-cell death and immune homeostasis
Ilia Voskoboinik,Ilia Voskoboinik,Mark J. Smyth,Mark J. Smyth,Joseph A. Trapani,Joseph A. Trapani +5 more
TLDR
Recent progress is described in defining the structure, function, biochemistry and cell biology of perforin.Abstract:
The granule exocytosis pathway of cytotoxic lymphocytes is crucial for immune surveillance and homeostasis. The trafficking of granule components, including the membrane-disruptive protein perforin, to the immunological synapse leads to the delivery of granule proteases (granzymes) into the target cell and its destruction through apoptosis. Several independent molecular abnormalities associated with defects of either granule trafficking or perforin function can cause cytotoxic lymphocyte dysfunction. In humans, inherited perforin mutations result in severe immune dysregulation that manifests as familial haemophagocytic lymphohistiocytosis. This Review describes recent progress in defining the structure, function, biochemistry and cell biology of perforin.read more
Citations
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Roles of the immune system in cancer: from tumor initiation to metastatic progression.
TL;DR: An update of recent accomplishments, unifying concepts, and future challenges to study tumor-associated immune cells, with an emphasis on metastatic carcinomas are provided.
Journal ArticleDOI
Targeting natural killer cells in cancer immunotherapy
Camille Guillerey,Camille Guillerey,Nicholas D. Huntington,Nicholas D. Huntington,Mark J. Smyth,Mark J. Smyth +5 more
TL;DR: Diverse approaches encompass the development of large-scale NK cell–expansion protocols for adoptive transfer, the establishment of a microenvironment favorable toNK cell activity, the redirection of NK cell activity against tumor cells and the release of inhibitory signals that limit NK cell function.
Journal ArticleDOI
Perforin and granzymes: function, dysfunction and human pathology
Ilia Voskoboinik,Ilia Voskoboinik,James C. Whisstock,James C. Whisstock,Joseph A. Trapani,Joseph A. Trapani +5 more
TL;DR: The current understanding of the structural, cellular and clinical aspects of perforin and granzyme biology is discussed, beginning to define and understand a range of human diseases that are associated with a failure to deliver active per forin to target cells.
Journal ArticleDOI
Familial and acquired hemophagocytic lymphohistiocytosis
TL;DR: In conclusion, awareness of the clinical symptoms and of the diagnostic criteria of HLH is crucial in order not to overlook HLH and to start life-saving therapy in time.
Journal ArticleDOI
NK cells and cancer immunosurveillance.
Inja Waldhauer,Alexander Steinle +1 more
TL;DR: The broadly accumulating evidence for a crucial contribution of NK cells to the immunosurveillance of tumours is reviewed and the molecular mechanisms that allowNK cells to distinguish malignant from healthy cells are reviewed.
References
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Journal ArticleDOI
Cytotoxicity mediated by T cells and natural killer cells is greatly impaired in perforin-deficient mice
David Kägi,Birgit Ledermann,Kurt Bürki,Peter Seiler,Bernhard Odermatt,Kristin J. Olsen,Eckhard R. Podack,Rolf M. Zinkernagel,Hans Hengartner +8 more
TL;DR: Perforin-deficient mice have been generated by homologous recombination to determine whether the effects of CDS+ cytolytic T cells and natural killer cells are mediated by pore formation involving perform, and perforin is therefore a key effector molecule for T-cell- and natural Killer- cell-mediated cy tolysis.
Journal ArticleDOI
Generalized lymphoproliferative disease in mice, caused by a point mutation in the fas ligand
Tomohiro Takahashi,Masato Tanaka,Camllynn I. Brannan,Nancy A. Jenkins,Neal G. Copeland,Takashi Suda,Shigekazu Nagata +6 more
TL;DR: The results indicate that lpr and gld are mutations in Fas and Fasl, respectively, and suggest important roles of the Fas system in development of T cells as well as cytotoxic T lymphocyte-mediated cytotoxicity.
Journal ArticleDOI
Functional significance of the perforin/granzyme cell death pathway
Joseph A. Trapani,Mark J. Smyth +1 more
TL;DR: Critically recent findings on cytotoxic granule-mediated cell death are evaluated to assess the functional significance of postulated cell-death pathways in appropriate pathophysiological contexts, including virus infection and susceptibility to experimental or spontaneous tumorigenesis.
Journal ArticleDOI
Perforin Gene Defects in Familial Hemophagocytic Lymphohistiocytosis
Susan E. Stepp,Dufourcq-Lagelouse R,Françoise Le Deist,Françoise Le Deist,Sadhna Bhawan,Stéphanie Certain,Porunelloor A. Mathew,Jan-Inge Henter,Michael J. Bennett,Alain Fischer,Alain Fischer,Geneviève de Saint Basile,Vinay Kumar +12 more
TL;DR: In this paper, the coding regions of the perforin gene of eight unrelated 10q21-22-linked FHL patients revealed homozygous nonsense mutations in four patients and missense mutations in the other four patients.
Journal ArticleDOI
Plasma Membrane Repair Is Mediated by Ca2+-Regulated Exocytosis of Lysosomes
TL;DR: It is shown that Ca(2+)-regulated exocytosis of lysosomes is required for the repair of plasma membrane disruptions and mediates the resealing of primary skin fibroblasts wounded during the contraction of collagen matrices.