Adenoviruses
Dongyou Liu in Laboratory Models for Foodborne Infections, 2017
One of the nonstructural proteins is encoded by L4 gene. The L4-100-kDa protein inhibits the translation of cellular mRNA by eliminating the cap-dependent translation pathway via binding to eukaryotic initiation factor 4G (eIF4G) and displacing Mnk1 from eIF4G. It also promotes translation of late viral mRNAs through ribosome shunting, which leads to nuclear accumulation of viral products for capsid assembly. The underlying mechanism for these functions is the interaction of L4-100 kDa with the tripartite leader (TL) sequence present in all the late viral transcripts and eIF4G, which is the scaffolding element of the cap-dependent translation initiation complex. In addition, L4-100-kDa protein not only acts as a chaperone facilitating hexon trimerization but also assists in nuclear accumulation of hexon trimers and in the scaffolding process of AdV capsid.98–101 Another function of L4-100 kDa is to prevent apoptosis induced by granzyme B in infected cells. Granzyme B, one of the lymphocyte granule serine proteases, catalyzes the cleavage and activation of several caspases which induce apoptotic events in infected cells. By interacting with granzyme B, the L4-100-kDa protein prevents access of substrates to the proteinase catalytic site through steric hindrance and inhibits its activity.102 A unique feature of L4-100 kDa is its posttranslational modification by arginine methyltransferase 1 (RPMT1). The methylation of L4-100 kDa has regulatory effects on modulating its interaction with hexon and TL mRNA as well as on promoting the capsid assembly.101
Tissue injury and repair
C. Simon Herrington in Muir's Textbook of Pathology, 2020
It is now recognized that there are other ways to stimulate the initiation pathway. We know, for example, that cytotoxic T lymphocytes release compounds such as granzyme B, which lead to the executioner phase without the involvement of a transmembrane death receptor complex or mitochondrial changes. Radiation and free radicals can also set the pathways in motion by inducing DNA damage and activating the tumour-suppressor TP53 gene, which codes for the p53 protein. p53 has been termed the ‘guardian of the genome’, arresting the cell cycle under these circumstances to allow time for DNA repair. If there is no repair, p53 induces apoptosis by upregulating the pro-apoptotic signals Bax and Apaf-1.
Sertoli cell immune regulation within the testis
C. Yan Cheng in Spermatogenesis, 2018
T cells and APCs are the main constituents of the cell-mediated immune response. T cells stimulated by APCs kill tissue via apoptosis mediated by the Fas-FasL or perforin-granzyme B pathways. Additionally, antigen-primed, CD4 T cells activate macrophages creating a proinflammatory environment that promotes cell death. Several in vitro and in vivo studies suggest that SCs modulate the overall immune response (Figure 6.4b). Transplanted SCs have the capability to escape cell death via apoptosis as they express SERPINA3N and SERPINB9,69–71 both inhibitors of the granzyme B apoptosis pathway. While controversial, it has also been reported that SCs can inhibit the Fas-FasL pathway (reviewed in Mital et al.72). In vitro experiments using rodent SC conditioned media (SCCM) demonstrated that SCs are capable of inhibiting the proliferation of activated lymphocytes (B and T cells).73–75 Treatment with SCCM significantly reduced the IL-2 production and IL-2 responsiveness by lymphocytes.73,74 Moreover, SCs express several immunoregualtory factors, such as galectin-1, indoleamine-pyrrole 2,3-dioxygenase (IDO), prostaglandin, transforming growth factor (TGF)-β),76–80 and have the capability to modulate the immune response in the testis or when transplanted ectopically. For instance, testicular macrophages and DCs express MHC-II and costimulatory molecules, implying these cells can mount an effective immune response. Yet upon lipopolysaccharide stimulation, rodent testicular macrophages express low levels of proinflammatory cytokines and high levels of the anti-inflammatory cytokine, IL-10 (reviewed in Winnall and Hedger81). Similarly, DCs isolated from the testis or testicular lymph nodes are unable to induce T cell proliferation.82
Predictive role of plasmatic biomarkers in advanced non-small cell lung cancer treated by nivolumab
Published in OncoImmunology, 2018
Adrien Costantini, Catherine Julie, Coraline Dumenil, Zofia Hélias-Rodzewicz, Julie Tisserand, Jennifer Dumoulin, Violaine Giraud, Sylvie Labrune, Thierry Chinet, Jean-François Emile, Etienne Giroux Leprieur
Granzyme B is a serine protease that is a mediator of target-cell apoptosis by cells such as NK cells and cytotoxic CD8+ T cells. Granzymes are delivered to the target cells via cytotoxic granules and are responsible for caspase-dependant apoptosis.24,25 Soluble Granzyme B has already been explored in the context of auto-immune diseases, showing that high levels of sGran B were associated with rheumatoid arthritis, myocardial infarction and lipid-rich carotid plaques.26-28 To our knowledge, this is the first time that sGran B concentrations have been evaluated in the plasma of NSCLC patients treated with nivolumab. We found that patients who presented with an objective response to nivolumab had significantly higher sGran B concentrations at nivolumab initiation than patients who were non-responders. This could reflect the activation of the CD8+ cytotoxic immune response, known to be associated with better response with ICIs. When analysing the variation of sGran B concentrations between nivolumab initiation and first tumour evaluation we found a tendency favouring patients with stable or decreasing concentrations for ORR, clinical benefit, OS and PFS. As for sPD-L1, an increase of sGran B at the beginning of the treatment could be the reflection of the persistence of a high tumour volume, with persistent CD8 lymphocytes activation and Granzyme B secretion. However, these hypotheses need to be validated in further studies.
Engaging natural killer cells for cancer therapy via NKG2D, CD16A and other receptors
Published in mAbs, 2023
Kerry A. Whalen, Kavya Rakhra, Naveen K. Mehta, Alexander Steinle, Jennifer S. Michaelson, Patrick A. Baeuerle
Among immune cells, NK cells are most closely related to cytotoxic T cells. The latter encompasses T cell subsets, including CD8+ and CD4+ T cells, gamma-delta T cells, and natural killer T (NKT) cells, all of which contain cytotoxic granules filled with cysteine proteases, called granzymes, and a pore-forming protein called perforin. NK cells, NKT cells and gamma-delta T cells belong to the innate immune system and serve as a first line of defense against pathogens, while CD8+ and CD4+ T cells are elements of the adaptive immune system, which are highly specific for pathogenic antigens, but first need to be primed, selected, and expanded in response to peptide antigen stimuli.11 Like T cells, NK cells are cytotoxic by virtue of having secretory granules filled with the same granzymes and a variant of perforin.12 Once delivered into a cytolytic synapse formed between NK cell and target cell, perforin forms a pore in the target cell membrane that enables transmembrane delivery of granzymes. Inside the target cell, granzyme B activates pro-caspases 3 and 7, eliciting programmed cell death, or apoptosis, while other granzymes such as granzyme A, H, K and M cleave numerous other protein substrates, causing target cell damage.13 Like T cells, NK cells also release inflammatory cytokines and chemokines upon activation.14
Immunotoxins and nanobody-based immunotoxins: review and update
Published in Journal of Drug Targeting, 2021
Mohammad Reza Khirehgesh, Jafar Sharifi, Fatemeh Safari, Bahman Akbari
For further deimmunising, human endogenous cytotoxic enzymes such as Granzyme B and RNase have been used in IT development. Granzyme B secretes from activated cytotoxic T-cells and natural killer cells. Translocation of Granzyme B into target cells leads to apoptosis induction [121–124]. Another strategy to reducing the immunogenicity of ITs is PEGylation, attaching polyethylene glycol to the target molecules. However, ITs PEGylation leads to reduced binding affinity and increased size [125,126]. Vascular leak syndrome (VLS) is one of the common side effects and dose-limiting toxicity of ITs. VLS is characterised by increased vascular permeability accompanied by extravasation of fluids and proteins, resulting in interstitial edoema and organ failure [127]. The conserved motif exists in RTA, PE and IL2 that induces VLS via binding to the endothelial cells [128]. Removing the motif may prevent VLS induction in IT therapy.
Related Knowledge Centers
- Basophil
- Cytotoxic T Cell
- Granzyme
- Inflammation
- Natural Killer Cell
- Serine Protease
- Smooth Muscle
- Apoptosis
- Perforin-1
- Mast Cell