In Vivo Elimination of MHC-I-Deficient Lymphocytes by Activated Natural Killer Cells Is Independent of Granzymes A and B

Regner, Matthias; Pavlinovic, Lisa; Müllbacher, Arno

doi:10.1371/journal.pone.0023252

Cited by 6 publications

(6 citation statements)

References 32 publications

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“…The most abundantly released Gzm at the site of the immunological synapse are GzmA and GzmB, which in vitro are proapoptotic molecules. While questions remain on the requirement of Gzm for NK‐cell and T‐cell‐mediated in vivo cytotoxicity , the Gzms also possess noncytolytic activities that can contribute to inactivation of intracellular pathogens (reviewed in ). The Fas receptor (Fas or CD95) is a transmembrane protein expressed on all nucleated cells, and induces apoptosis upon engagement of Fas ligand expressed on cytotoxic effector cells.…”

Section: Introductionmentioning

confidence: 99%

Cytolytic effector pathways and IFN‐γ help protect against Japanese encephalitis

2013

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Japanese encephalitis, caused by infection with the neurotropic flavivirus, Japanese encephalitis virus (JEV), is among the most important viral encephalitides in Asia. While previous studies established an essential role of Ab and type I IFN, it is still unclear if the cell-mediated immune responses, through their direct antiviral effector functions, contribute to protection against the fatal disease. We report here that mice defective in both the granule exocytosis and death receptor pathways of cytotoxicity display increased susceptibility to JEV. The two cell contact-dependent cytotoxic effector mechanisms act redundantly within the CNS to reduce disease severity. We also demonstrate that IFN-γ is critical in recovery from primary infection with JEV by a mechanism involving suppression of virus growth in the CNS, and that T cells are the main source of the cytokine that promotes viral clearance from the brain. Finally, we show by in vivo depletion of NK cells that this innate immune cell population is dispensable for control of JEV infection in the periphery and in the CNS. Accordingly, cell contact-dependent cytolytic and IFN-γ-dependent noncytolytic clearance of virus mediated by T cells trafficking into the CNS help in recovery from lethal infection in a mouse model of Japanese encephalitis. Keywords: Fas receptor r Flavivirus r Granzyme r Mouse model r Viral encephalitisAdditional supporting information may be found in the online version of this article at the publisher's web-site IntroductionTo explore the immunological correlates for recovery from primary infection with the medically important neurotropic flavivirus, Japanese encephalitis virus (JEV), we have developed an adult mouse model that resembles the physiological route of virus transmission to the mammalian host by the bite of an infected mosquito [1]. We found that s.c. deposition of a small dose of JEV into the footpad of C57BL/6 (B6) mice resulted in neuroCorrespondence: Dr. Mario Lobigs e-mail: m.lobigs@uq.edu.au invasive disease that was lethal in ∼60% of animals. Mice staged T-cell-independent IgM and T-cell-dependent IgG responses that became detectable at days 4 and 8 postinfection (pi) respectively, and neutralized virus infectivity in vitro [1]. This early and sustained humoral immune response is considered absolutely essential for survival of infection with JEV and related flaviviruses, because infections of B-cell-deficient (μMT) mice were uniformly lethal [1,2]. In addition to Ab, type I IFN responses are indispensable in the control of JEV infection [3,4]. On the other hand, the role of CD8 + T cells in recovery from Japanese encephalitis (JE) remains ambiguous. While JEV infection resulted in extensive activation and migration of CD8 + T cells into the CNS, they did not provide a significant survival advantage based on mortality rates in groups of mice subjected to in vivo depletion of this Infection of the CNS with JEV triggers extensive neuronal death induced directly by viral infection as well as bystander damage resulting fr...

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Section: Introductionmentioning

confidence: 99%

Cytolytic effector pathways and IFN‐γ help protect against Japanese encephalitis

2013

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“…We show herein that this mouse strain is on a mixed 6J/6N background and contains full length Nnt, with the NNT protein involved in ROS regulation. For example, T cell activities can be regulated by ROS in a range of settings (Chen et al, 2016;Franchina et al, 2018;Murphy and Siegel, 2013;Yarosz and Chang, 2018), perhaps contributing to the controversy (Ebnet et al, 1995;Joeckel and Bird, 2014;Regner et al, 2009;Regner et al, 2011;Smyth et al, 2003) regarding the role of lymphocyte-derived GzmA as a mediator of cellular cytotoxicity (Pardo et al, 2002;Pardo et al, 2004;Shresta et al, 1999;Susanto et al, 2013). Whether all the pheontypes reported for GzmA -/mice were compromised by Nnt (or mixed the background) remains unclear and may require new experiments to resolve, similar to those described herein for CHIKV arthritis.…”

Section: Discussionmentioning

confidence: 77%

“…For instance, control of viral infections can be compromised in GzmA -/mice (Loh et al, 2004;Mullbacher et al, 1996;Pereira et al, 2000;Riera et al, 2000), with cytotoxic lymphocytes from these mice reported to be less able to kill target cells (Pardo et al, 2002;Pardo et al, 2004;Shresta et al, 1999;Susanto et al, 2013). Like granzyme B (GzmB), GzmA has thus been classified as a cytotoxic granzyme (Golstein and Griffiths, 2018;Mpande et al, 2018;Muraro et al, 2017;Zhou et al, 2020), although in several studies a role for GzmA in mediating cellular cytotoxicity was not observed (Ebnet et al, 1995;Joeckel and Bird, 2014;Regner et al, 2009;Regner et al, 2011;Smyth et al, 2003). In a range of settings GzmA has also been associated with the promotion of inflammation, providing an additional or alternative view of its physiological role, although consensus on mechanisms has remained elusive (Metkar et al, 2008;Park et al, 2020;Santiago et al, 2020;Santiago et al, 2017;Schanoski et al, 2019;Shimizu et al, 2019; van Daalen et al, 2020;Wensink et al, 2015;Wilson et al, 2017), with a number of potential intracellular and extracellular targets for GzmA reported.…”

Section: Introductionmentioning

confidence: 99%

An inconvenient association between granzyme A and Nicotinamide Nucleotide Transhydrogenase

Rawle

Dumenil

et al. 2021

Preprint

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Granzyme A (GzmA) is a serine protease secreted by cytotoxic lymphocytes, with GzmA-/- mouse studies informing our understanding of GzmAs physiological function. We show herein that GzmA-/- mice have a mixed C57BL/6J and C57BL/6N background and retain the full length Nicotinamide Nucleotide Transhydrogenase (Nnt) gene, whereas Nnt is truncated in C57BL/6J mice. Chikungunya viral arthritis was substantially ameliorated in GzmA-/- mice; however, the presence of Nnt, rather than loss of GzmA, was responsible for this phenotype by constraining lymphocyte infiltration. A new CRISPR active site mutant C57BL/6J GzmAS211A mouse provided the first insights into GzmAs bioactivity free of background issues, with circulating proteolytically active GzmA promoting immune-stimulating and pro-inflammatory signatures. Remarkably, k-mer mining of the Sequence Read Archive illustrated that ~27% of Run Accessions and ~38% of Bioprojects listing C57BL/6J as the mouse strain, had Nnt sequencing reads inconsistent with a C57BL/6J background. The Nnt issue has clearly complicated our understanding of GzmA and may similarly have influenced studies across a broad range of fields.

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“…To determine if the alterations in NK Ly49 repertoire correlated with NK cell killing ability, we analyzed Sostdc1 -/- NK cell cytotoxicity with novel FCM-based in vivo and in vitro killing assays ( Figure 2 and Supplemental Figure 3A-3E ). Beta-2 microglobulin knockout (β 2 m -/- ) cells express little to no cell surface class I major histocompatibility complex (MHC I) molecules and therefore are sensitive targets for NK cell killing 28 . To test NK cell killing in vivo , we pre-activated NK cells in Sostdc1 -/- and WT control mice with poly(I:C) 29 (Figure 2A) and challenged them with equal numbers of β 2 m -/- and beta-2 microglobulin-sufficient (β 2 m +/+ ) target cells, each labeled with two different fluorochromes ( Figure 2B ).…”

Section: Resultsmentioning

confidence: 99%

Sostdc1 regulates natural killer cell maturation and cytotoxicity

Millan

Elizaldi

Lee

et al. 2018

Preprint

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Natural killer (NK) cells are specialized lymphocytes with the innate ability to eliminate virally infected and cancerous cells, but the mechanisms that control NK cell development and cytotoxicity are incompletely understood. We identified novel roles for Sclerostin domain containing-1 (Sostdc1) in NK cell development and function. Sostdc1knockout (Sostdc1 -/-) mice display a progressive accumulation of transitional NK cells (CD27 + CD11b + , tNK) with age, indicating a partial developmental block. The Ly49 repertoire on NK cells in Sostdc1 -/mice is also changed. Lower frequencies of Sostdc1 -/splenic tNKs express inhibitory Ly49G2 receptors, but higher frequencies express activating Ly49H and Ly49D receptors. However, the frequencies of Ly49I + , G2 + , H + and D + populations were universally decreased at the most mature (CD27 -CD11b + , mNK) stage. We hypothesized that the Ly49 repertoire in Sostdc1 -/mice would correlate with NK killing ability, and observed that Sostdc1 -/-NK cells are hyporesponsive against MHC-I-deficient cell targets in vitro and in vivo, despite higher CD107a surface levels and similar IFN expression to controls. Consistent with Sostdc1's known role in the regulation of Wnt signaling, high levels of Wnt coactivators Tcf7 and Lef1 were observed in Sostdc1 -/-NK cells. Expression of the NK development gene Id2 was decreased in Sostdc1 -/-iNK and tNK cells, but we observed no changes in Eomes and Tbx21 expression. Reciprocal bone marrow transplant experiments showed that Sostdc1 regulates NK cell maturation and expression of Ly49 receptors in a cellextrinsic fashion from both non-hematopoietic and hematopoietic sources. Taken together, these data support a role for Sostdc1 in the regulation of NK cell maturation, and NK cell cytotoxicity, and identify potential NK cell niches.

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In Vivo Elimination of MHC-I-Deficient Lymphocytes by Activated Natural Killer Cells Is Independent of Granzymes A and B

Cited by 6 publications

References 32 publications

Cytolytic effector pathways and IFN‐γ help protect against Japanese encephalitis

Cytolytic effector pathways and IFN‐γ help protect against Japanese encephalitis

An inconvenient association between granzyme A and Nicotinamide Nucleotide Transhydrogenase

Sostdc1 regulates natural killer cell maturation and cytotoxicity

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