ORCID Profile
0000-0001-8178-9522
Current Organisation
University of Melbourne
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Publisher: Oxford University Press (OUP)
Date: 24-01-2018
Abstract: It is widely accepted that cytotoxic T and NK cells store effector proteins including granzymes, perforin and Fas ligand (FasL) in intracellular granules, often referred to as secretory lysosomes. Upon target cell encounter, these organelles are transported to the cytotoxic immunological synapse, where they fuse with the plasma membrane to release the soluble effector molecules and to expose transmembrane proteins including FasL on the cell surface. We previously described two distinct species of secretory vesicles in T and NK cells that differ in size, morphology and protein loading, most strikingly regarding FasL and granzyme B. We now show that the signal requirements for the mobilization of one or the other granule also differ substantially. We report that prestored FasL can be mobilized independent of extracellular Ca2+, whereas the surface exposure of lysosome-associated membrane proteins (L s CD107a and CD63) and the release of granzyme B are calcium-dependent. The use of selective inhibitors of actin dynamics unequivocally points to different transport mechanisms for in idual vesicles. While inhibitors of actin polymerization/dynamics inhibit the surface appearance of prestored FasL, they increase the activation-induced mobilization of CD107a, CD63 and granzyme B. In contrast, inhibition of the actin-based motor protein myosin 2a facilitates FasL-, but impairs CD107a-, CD63- and granzyme B mobilization. From our data, we conclude that distinct cytotoxic effector granules are differentially regulated with respect to signaling requirements and transport mechanisms. We suggest that a T cell might ‘sense’ which effector proteins it needs to mobilize in a given context, thereby increasing efficacy while minimizing collateral damage.
Publisher: Public Library of Science (PLoS)
Date: 09-08-2017
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 06-01-2020
DOI: 10.1002/HEP4.1463
Abstract: The transcription factor promyelocytic leukemia zinc finger protein (PLZF) is involved in the development of natural killer (NK) cells and innate lymphoid cells, including liver‐resident NK cells in mice. In human NK cells, the role of PLZF in liver residency is still unknown. Expression of PLZF in matched human peripheral blood‐ and liver‐derived NK cells and the association of PLZF expression with surface molecules and transcription factors relevant for tissue residency were investigated using multiparameter flow cytometry and assessing single‐cell messenger RNA (mRNA) levels. Intrahepatic cluster of differentiation (CD)56 bright NK cells expressed significantly higher levels of PLZF than peripheral blood CD56 bright NK cells, which were predominantly PLZF lo . Expression of PLZF was highest within C‐X‐C motif chemokine receptor 6 (CXCR6) + CD69 + liver‐resident NK cells among intrahepatic CD56 bright NK cell populations. Association of PLZF with liver‐residency markers was also reflected at mRNA levels. A small PLZF hi CD56 bright NK cell population was identified in peripheral blood that also expressed the liver‐residency markers CXCR6 and CD69 and shared functional characteristics with liver‐resident NK cells. Conclusion: PLZF is implicated as part of a transcriptional network that promotes liver residency of human NK cells. Expression of liver‐homing markers on peripheral blood PLZF hi CD56 bright NK cells identifies an intermediate population potentially contributing to the maintenance of liver‐resident NK cells.
Publisher: American Society for Clinical Investigation
Date: 22-03-2021
Publisher: Elsevier BV
Date: 08-2021
Publisher: Elsevier BV
Date: 11-2018
DOI: 10.1053/J.GASTRO.2018.07.019
Abstract: Killer-cell immunoglobulin-like receptors (KIRs) are transmembrane glycoproteins expressed by natural killer (NK) cells. Binding of KIR3DS1 to its recently discovered ligand, HLA-F, activates NK cells and has been associated with resolution of hepatitis C virus (HCV) infection. We investigated the mechanisms by which KIR3DS1 contributes to the antiviral immune response. Using cell culture systems, mice with humanized livers, and primary liver tissue from HCV-infected in iduals, we found that the KIR3DS1 ligand HLA-F is up-regulated on HCV-infected cells, and that interactions between KIR3DS1 and HLA-F contribute to NK cell-mediated control of HCV. Strategies to promote interaction between KIR3DS1 and HLA-F might be developed for treatment of infectious diseases and cancer.
Publisher: Public Library of Science (PLoS)
Date: 20-07-2018
Publisher: Elsevier BV
Date: 04-2021
Publisher: Frontiers Media SA
Date: 07-06-2019
Publisher: Elsevier BV
Date: 10-2019
DOI: 10.1016/J.JHEP.2019.05.023
Abstract: Primary sclerosing cholangitis (PSC) is an idiopathic, chronic cholestatic liver disorder characterized by biliary inflammation and fibrosis. Increased numbers of intrahepatic interferon-γ- (IFNγ) producing lymphocytes have been documented in patients with PSC, yet their functional role remains to be determined. Liver tissue s les were collected from patients with PSC. The contribution of lymphocytes to liver pathology was assessed in Mdr2 Patients with PSC showed increased IFNγ serum levels and elevated numbers of hepatic CD56 IFNγ changed the phenotype of hepatic CD8 Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease characterized by biliary inflammation and fibrosis, whose current medical treatment is hardly effective. We observed an increased interferon (IFN)-γ response in patients with PSC and in a mouse model of sclerosing cholangitis. IFNγ changed the phenotype of hepatic CD8
Publisher: Wiley
Date: 27-02-2019
Abstract: The pathogenesis of primary sclerosing cholangitis (PSC), an autoimmune liver disease, remains unknown. The aim of this study was to characterize peripheral blood and intrahepatic NK cells from patients with PSC. Peripheral blood s les from patients with PSC, other autoimmune liver diseases, and from healthy control in iduals were used, as well as liver tissues from PSC patients undergoing liver transplantation. Multiparameter flow cytometry showed that peripheral blood NK cells from PSC patients were significantly enriched for CCR7
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 10-2020
DOI: 10.1002/HEP.31140
Abstract: T cells from patients with primary sclerosing cholangitis (PSC) show a prominent interleukin (IL)‐17 response upon stimulation with bacteria or fungi, yet the reasons for this dominant T‐helper 17 (Th17) response in PSC are not clear. Here, we analyzed the potential role of monocytes in microbial recognition and in skewing the T‐cell response toward Th17. Monocytes and T cells from blood and livers of PSC patients and controls were analyzed ex vivo and in vitro using transwell experiments with cholangiocytes. Cytokine production was measured using flow cytometry, enzyme‐linked immunosorbent assay, RNA in situ hybridization, and quantitative real‐time PCR. Genetic polymorphisms were obtained from ImmunoChip analysis. Following e x vivo stimulation with phorbol myristate acetate/ionomycin, PSC patients showed significantly increased numbers of IL‐17A–producing peripheral blood CD4 + T cells compared to PBC patients and healthy controls, indicating increased Th17 differentiation in vivo . Upon stimulation with microbes, monocytes from PSC patients produced significantly more IL‐1β and IL‐6, cytokines known to drive Th17 cell differentiation. Moreover, microbe‐activated monocytes induced the secretion of Th17 and monocyte‐recruiting chemokines chemokine (C‐C motif) ligand (CCL)‐20 and CCL‐2 in human primary cholangiocytes. In livers of patients with PSC cirrhosis, CD14 hi CD16 int and CD14 lo CD16 hi monocytes/macrophages were increased compared to alcoholic cirrhosis, and monocytes were found to be located around bile ducts. PSC patients show increased Th17 differentiation already in vivo . Microbe‐stimulated monocytes drive Th17 differentiation in vitro and induce cholangiocytes to produce chemokines mediating recruitment of Th17 cells and more monocytes into portal tracts. Taken together, these results point to a pathogenic role of monocytes in patients with PSC.
Publisher: Oxford University Press (OUP)
Date: 19-02-2019
Abstract: NK cells have been implicated to affect the outcome of numerous liver diseases. In particular, members of the killer-cell Ig-like receptor (KIR) family, predominantly expressed by NK cells, have been associated with the outcome of hepatitis C virus infection and clearance of hepatocellular carcinoma. Inhibitory KIRs tune NK cell function through interaction with HLA class I, a process termed education. Nevertheless, the impact of the hepatic environment on NK cell education is incompletely understood. Therefore, we investigated the composition and function of hepatic KIR-expressing NK cells. Matched PBMC and hepatic lymphocytes were isolated from 20 in iduals undergoing liver surgery and subsequently phenotypically analyzed for expression of KIRs and markers for tissue residency using flow cytometry. NK cell function was determined by co-culturing NK cells with the target cell line 721.221 and subsequent assessment of CD107a, IFN-γ, and TNF-α expression. Liver-resident CXCR6+/CD56Bright NK cells lacked KIRs and were predominantly educated through NKG2A, while CXCR6−/CD16+ NK cells expressed KIRs and resembled peripheral blood NK cells. Hepatic NK cells showed lower response rates compared to peripheral blood NK cells in particular, CXCR6+ NK cells were hyporesponsive to stimulation with target cells. The high proportion of educated NK cells in both subsets indicates the importance of self-inhibitory receptors for the balance between maintenance of self-tolerance and functional readiness. However, the reduced functionality of hepatic NK cells may reflect the impact of the tolerogenic hepatic environment on NK cells irrespective of NK cell education.
No related grants have been discovered for Tobias Poch.