Granulysin species segregate to different lysosome-related effector vesicles (LREV) and get mobilized by either classical or non-classical degranulation

Lettau, Marcus; Dietz, Michelle; Dohmen, Katharina; Leippe, Matthias; Kabelitz, Dieter; Janßen, Ottmar

doi:10.1016/j.molimm.2018.12.031

Cited by 13 publications

(14 citation statements)

References 32 publications

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“…2 In addition, it has been reported the antimicrobial effects of 15 kDa granulysin 3 and the activationinduced and selective release of both isoforms. 4 The main role of the 9 kDa cytotoxic isoform is the killing of intracellular bacteria such as M. Tuberculosis in concert with perforin. 5 Recently, it has been also suggested that granulysin makes pores on the surface of bacteria and protozoan parasites, facilitating lysis exerted by granzyme B.…”

Section: Introductionmentioning

confidence: 99%

Anti-tumoral potential of a human granulysin-based, CEA-targeted cytolytic immunotoxin

et al. 2019

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Granulysin is a protein present in the granules of human cytotoxic T lymphocytes (CTL) and natural killer (NK) cells, with cytolytic activity against microbes and tumors. Previous work demonstrated the therapeutic effect of intratumoral injection of recombinant granulysin using in vivo models of breast cancer and multiple myeloma. In the present work we have developed a granulysin gene fusion to the anticarcinoembryonic antigen (CEA/CEACAM5) single chain Fv antibody fragment MFE23. Both granulysin and the granulysin-based immunotoxin were expressed in Pichia pastoris. The immunotoxin specifically recognized CEA, purified or expressed on the cell surface. Moreover, the bioactivity of the immunotoxin against several CEA + cell lines was higher than that of granulysin alone. Granulysin and the immunotoxin were tested as a treatment in in vivo xenograft models in athymic mice. When injected intratumorally, both granulysin and the immunotoxin were able to inhibit tumor growth. Furthermore, systemic administration of the immunotoxin demonstrated a decrease in tumor growth in a CEA + tumor-bearing mouse model, whereas granulysin did not exhibit a therapeutic effect. This is the first granulysin-based immunotoxin and the present work constitutes the proof of concept of its therapeutic potential.

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Section: Introductionmentioning

confidence: 99%

Anti-tumoral potential of a human granulysin-based, CEA-targeted cytolytic immunotoxin

et al. 2019

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“…CD8 + αβ T cells, γδ T cells, NK cells), also CD4 + T cells develop secretory granules when activated and expanded in vivo or in vitro ( 20 , 21 ). However, as we have pointed out in several studies, classical cytotoxic cells carry most of the mentioned vesicle-associated proteins in higher abundance than cytotoxic CD4 + T cells ( 7 , 19 , 22 ).…”

Section: Introduction – Secretory Vesicles In Hematopoietic Cellsmentioning

confidence: 75%

“…According to our observations, GNLY may in fact serve as a prototypic marker for the detection and analysis of different LREV species ( 7 ). GNLY is differentially distributed in individual subsets of T cells and NK cells.…”

Section: Gnly Variants As Markers For Lrev Subsets and Differential Degranulationmentioning

confidence: 91%

“…Examples include antigen-presenting cells (APC) such as macrophages, dendritic cells or B cells containing vesicular MHC compartments for the storage, processing and presentation of antigen-loaded MHC-molecules ( 1 ), basophils and mast cells secreting histamine and serotonin in response to Fc receptor ligation or chemotactic agents ( 2 ), and platelets releasing effector molecules such as serotonin and P-selectin for blood coagulation ( 3 ). In cytotoxic T cells (CTL) and Natural Killer (NK) cells, so-called lytic granules comprise lysosomal storage and effector compartments that – among others - carry pore-forming perforin (PRF) or granulysin (GNLY), proteolytically active granzymes (GRZs), and apoptosis-inducing death ligands such as FasL to warrant an effective target cell lysis ( 4 – 7 ). Thereby, CTL and NK cells form the prominent effector cell populations of the immune system to control virus-infected or tumor cells.…”

Section: Introduction – Secretory Vesicles In Hematopoietic Cellsmentioning

confidence: 99%

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Intra- and Extracellular Effector Vesicles From Human T And NK Cells: Same-Same, but Different?

Lettau

Janßen

2021

Front. Immunol.

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Cytotoxic T lymphocytes (CTL) and Natural Killer (NK) cells utilize an overlapping effector arsenal for the elimination of target cells. It was initially proposed that all cytotoxic effector proteins are stored in lysosome-related effector vesicles (LREV) termed “secretory lysosomes” as a common storage compartment and are only released into the immunological synapse formed between the effector and target cell. The analysis of enriched LREV, however, revealed an uneven distribution of individual effectors in morphologically distinct vesicular entities. Two major populations of LREV were distinguished based on their protein content and signal requirements for degranulation. Light vesicles carrying FasL and 15 kDa granulysin are released in a PKC-dependent and Ca2+-independent manner, whereas dense granules containing perforin, granzymes and 9 kDa granulysin require Ca2+-signaling as a hallmark of classical degranulation. Notably, both types of LREV do not only contain the mentioned cytolytic effectors, but also store and transport diverse other immunomodulatory proteins including MHC class I and II, costimulatory and adhesion molecules, enzymes (i.e. CD26/DPP4) or cytokines. Interestingly, the recent analyses of CTL- or NK cell-derived extracellular vesicles (EV) revealed the presence of a related mixture of proteins in microvesicles or exosomes that in fact resemble fingerprints of the cells of origin. This overlapping protein profile indicates a direct relation of intra- and extracellular vesicles. Since EV potentially also interact with cells at distant sites (apart from the IS), they might act as additional effector vesicles or intercellular communicators in a more systemic fashion.

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“…Recently, this group further refined their findings, showing that release of 15 kDa granulysin requires PKC only, while release of 9 kDa granulysin, in addition to other cytotoxic molecules, is dependent on calcium (14) . This suggests that an immune cell can 'sense' which granule to mobilise and release, dependent on the function the cell wishes to elicit.…”

Section: Structure and Subcellular Location Of Granulysinmentioning

confidence: 91%

Granulysin: The attractive side of a natural born killer

Sparrow

Bodman‐Smith

2020

Immunology Letters

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First discovered in the 1980's, granulysin has until recently been thought of solely as an effector molecule present within cytotoxic immune cell populations, and involved in the direct killing of pathogens and infected or transformed eukaryotic cells. However, recent research has suggested an additional role of granulysin, in particular the 15 kDa isoform. While 9 kDa granulysin is broadly cytotoxic and capable of the direct killing of bacteria and other pathogens, the 15 kDa isoform of this molecule has been shown to function as an immune 'alarmin', causing the maturation and migration of antigen-presenting cells and other cells of the immune system. This dual function of granulysin indirectly increases the immune response to an infection or tumour, and therefore escalates its importance in the immune system. Here we review the different roles of granulysin, both as a cytotoxic molecule, and as a modulator of the immune system, and discuss the impact this molecule may have on the response to tumour and infection.

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Granulysin species segregate to different lysosome-related effector vesicles (LREV) and get mobilized by either classical or non-classical degranulation

Cited by 13 publications

References 32 publications

Anti-tumoral potential of a human granulysin-based, CEA-targeted cytolytic immunotoxin

Anti-tumoral potential of a human granulysin-based, CEA-targeted cytolytic immunotoxin

Intra- and Extracellular Effector Vesicles From Human T And NK Cells: Same-Same, but Different?

Granulysin: The attractive side of a natural born killer

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