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Sertoli cell immune regulation within the testis
Published in C. Yan Cheng, Spermatogenesis, 2018
Gurvinder Kaur, Kandis Wright, Robin Hannah Greer, Karl Mueller, Allan Haynes, Jannette M. Dufour
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
SERPINB9 is commonly amplified and high expression in cancer cells correlates with poor immune checkpoint blockade response
Published in OncoImmunology, 2022
Sofía Ibáñez-Molero, Alex van Vliet, Joanna Pozniak, Karlijn Hummelink, Alexandra M. Terry, Kim Monkhorst, Joyce Sanders, Ingrid Hofland, Ewout Landeloos, Yannick Van Herck, Oliver Bechter, Thomas Kuilman, Weiwei Zhong, Jean-Christophe Marine, Lodewyk Wessels, Daniel S. Peeper
SERPINB9 is a serine protease inhibitor of the effector molecules granzyme B and caspase.6,8,15,20–23 Given the difference in baseline expression of SERPINB9 in the cell line panel we examined the differences in the transcriptomic landscape of SERPINB9high and SERPINB9low cells. We performed pathway enrichment analysis on the log2-fold changes from the DE genes identified above (Figure 1d) and found that, amongst several other pathways, the epithelial to mesenchymal transition (EMT) pathway was significantly enriched in SERPINB9high cells (Figure 4a). We evaluated the expression of an EMT pan-cancer signature previously established14 in the cell line panel. We observed that higher levels of SERPINB9 corresponded with higher expression of mesenchymal genes, whereas low levels of SERPINB9 correlated with higher expression of epithelial genes in the tumor cells (Figure 4b). We quantified this correlation by calculating an epithelial/mesenchymal score (EMT score) from the average normalized expression of epithelial genes divided by the average normalized expression of mesenchymal genes. The EMT score was inversely correlated with SERPINB9 expression across our cell panel (Figure 4c).
Granzyme B as a therapeutic target: an update in 2022
Published in Expert Opinion on Therapeutic Targets, 2022
Alexandre Aubert, Michael Lane, Karen Jung, David J. Granville
SERPINB9 (PI-9, and its murine ortholog Serpinb9 or spi6) is a 42 kDa clade B serpin (also known as the Ov-serpin subfamily) that inhibits intracellular GzmB proteolytic activity. Expressed by CTL, NK cells, as well as by other immune cells expressing GzmB (including mast cells), SERPINB9 is found in the nucleus and the cytoplasm where it usually co-localizes with GzmB-containing granules [82,83]. More precisely, SERPINB9 and GzmB physically interact to form a molecular complex that maintains the protease in an inactive form, thus preventing unintended and self-induced GzmB-dependent immune-cell apoptosis [84,85]. Similar to other clade B serpins, SERPINB9 lacks a secretory signal peptide and is consequently retained in the intracellular compartment [86]. In fact, only one study reported circulating SERPINB9 in serum from patients with cytomegalovirus infection thus far [87], but this epiphenomenon is most likely due to passive release from necrotic cells. In addition, and due to its intracellular nature, SERPINB9 is predicted to be sensitive to extracellular oxidation, thus rendering it an unlikely extracellular inhibitor for GzmB [43].
Granzyme B as a therapeutic target for wound healing
Published in Expert Opinion on Therapeutic Targets, 2019
Christopher T. Turner, Sho Hiroyasu, David J. Granville
Elevated extracellular granzyme B is observed in many dermatological conditions, including atopic dermatitis [21], bullous diseases [22], UV damaged skin [23], keloids and hypertrophic scars [24]. Approximately one-third of granzyme B escapes from the immunological synapse and into the extracellular milieu during CTL/target-cell engagement [25]. In addition to CTL and NK cells, other immune cells also express granzyme B, including macrophages [26], T-regulatory cells (Tregs) [27], basophils [28], CD4+ cells [29], mast cells [30], dendritic cells [31] and neutrophils [32]. Saliently, many of these immune cell types do not secrete perforin and/or do not form immunological synapses with target cells [33]. Non-immune cells also express granzyme B, including keratinocytes [34], primary spermatocytes [35], chondrocytes [36], Type II pneumocytes [37], syncytial trophoblasts [35] and granulosa cells [38]. The lack of endogenous extracellular granzyme B inhibitors in human bio-fluids suggests it retains its activity in human plasma and remains unregulated [39]. In bronchoalveolar lavage samples, none of the major serine protease inhibitors, including secretory leukocyte protease inhibitor, α1-antitrypsin, and elafin, were found to inhibit granzyme B activity [40]. One potent intracellular inhibitor of granzyme B has been found in human cells, namely serpinB9, or also known as protease inhibitor-9. However, serpinB9 does not contain a secretory signal peptide and is therefore unlikely to be trafficked through the secretory pathway and released extracellularly [41]. Together, granzyme B is secreted into the extracellular milieu and remains unregulated, and consequently, have led us to re-evaluate the role of granzyme B in health and disease.