Mouse granzyme K has pro-inflammatory potential

Joeckel, Lars T.; Wallich, Reinhard; Martin, Praxedis; Sánchez-Martínez, Diego; Weber, Felix; Martin, Stefan F.; Borner, Christoph; Pardo, Julián; Froelich, Christopher J.; Simon, Markus M.

doi:10.1038/cdd.2011.5

Cited by 93 publications

(143 citation statements)

References 45 publications

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“…In addition, it has been shown recently that cord blood contains a small proportion of Th1, Th2, and Th17 effector memory-like CD4 + αβ T cells, indicating the functional plasticity of this subset (74). We also showed that fetal blood Vγ9Vδ2 T cells express a particular pattern of granzymes with high coexpression of granzymes A and K but no expression of the classical killer granzyme B (75,76). Perforin was enriched in Vγ9Vδ2 T cells at the RNA level but not at the protein level, in contrast to adult Vγ9Vδ2 T cells, which are known to express perforin, granzyme B, and granulysin protein (3).…”

Section: Discussionmentioning

confidence: 59%

Effector Vγ9Vδ2 T cells dominate the human fetal γδ T-cell repertoire

Dimova

Brouwer

Gosselin

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

187

215

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γδ T cells are unconventional T cells recognizing antigens via their γδ T-cell receptor (TCR) in a way that is fundamentally different from conventional αβ T cells. γδ T cells usually are divided into subsets according the type of Vγ and/or Vδ chain they express in their TCR. T cells expressing the TCR containing the γ-chain variable region 9 and the δ-chain variable region 2 (Vγ9Vδ2 T cells) are the predominant γδ T-cell subset in human adult peripheral blood. The current thought is that this predominance is the result of the postnatal expansion of cells expressing particular complementary-determining region 3 (CDR3) in response to encounters with microbes, especially those generating phosphoantigens derived from the 2-C-methyl-d-erythritol 4-phosphate pathway of isoprenoid synthesis. However, here we show that, rather than requiring postnatal microbial exposure, Vγ9Vδ2 T cells are the predominant blood subset in the second-trimester fetus, whereas Vδ1+ and Vδ3+ γδ T cells are present only at low frequencies at this gestational time. Fetal blood Vγ9Vδ2 T cells are phosphoantigen responsive and display very limited diversity in the CDR3 of the Vγ9 chain gene, where a germline-encoded sequence accounts for >50% of all sequences, in association with a prototypic CDR3δ2. Furthermore, these fetal blood Vγ9Vδ2 T cells are functionally preprogrammed (e.g., IFN-γ and granzymes-A/K), with properties of rapidly activatable innatelike T cells. Thus, enrichment for phosphoantigen-responsive effector T cells has occurred within the fetus before postnatal microbial exposure. These various characteristics have been linked in the mouse to the action of selecting elements and would establish a much stronger parallel between human and murine γδ T cells than is usually articulated.

show abstract

Section: Discussionmentioning

confidence: 59%

Effector Vγ9Vδ2 T cells dominate the human fetal γδ T-cell repertoire

Dimova

Brouwer

Gosselin

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

187

215

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“…[8][9][10]24 Here, we have demonstrated that cell death can be induced when mGzmA is delivered by NKs via authentic CL/target cell interactions.…”

Section: Discussionmentioning

confidence: 79%

“…5,6 This oxidative stress is predicted to cause translocation of the SET complex into the nucleus, where GzmA cleaves components of the SET complex and induces DNA damage through single-stranded nicking, resulting in cell death. 5,7 However, these findings have been difficult to corroborate and recent studies from several independent groups using recombinant or native protease have reported that GzmA has little cytotoxicity [8][9][10] or that GzmA may simply enhance Pfp-mediated membranolysis. 8 In contrast, studies using GzmB À / À CTL suggest that GzmA does have a role in target cell death.…”

mentioning

confidence: 99%

Mouse granzyme A induces a novel death with writhing morphology that is mechanistically distinct from granzyme B-induced apoptosis

et al. 2013

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Human and mouse granzyme (Gzm)B both induce target cell apoptosis in concert with pore-forming perforin (Pfp); however the mechanisms by which other Gzms induce non-apoptotic death remain controversial and poorly characterised. We used timelapse microscopy to document, quantitatively and in real time, the death of target cells exposed to primary natural killer (NK) cells from mice deficient in key Gzms. We found that in the vast majority of cases, NK cells from wild-type mice induced classic apoptosis. However, NK cells from syngeneic Gzm B-deficient mice induced a novel form of cell death characterised by slower kinetics and a pronounced, writhing, 'worm-like' morphology. Dying cells initially contracted but did not undergo membrane blebbing, and annexin-V staining was delayed until the onset of secondary necrosis. As it is different from any cell death process previously reported, we tentatively termed this cell death 'athetosis'. Two independent lines of evidence showed this alternate form of death was due to Gzm A: first, cell death was revealed in the absence of Gzm B, but was completely lost when the NK cells were deficient in both Gzm A and B; second, the athetotic morphology was precisely reproduced when recombinant mouse Gzm A was delivered by an otherwise innocuous dose of recombinant Pfp. Gzm A-mediated athetosis did not require caspase activation, early mitochondrial disruption or generation of reactive oxygen species, but did require an intact actin cytoskeleton and was abolished by latrunculin B and mycalolide B. This work defines an authentic role for mouse Gzm A in granule-induced cell death by cytotoxic lymphocytes.

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“…Human gzmB has been shown to induce cell death in Jurkat cells by degradation of Mcl-1 and subsequent release of proapoptotic Bim (22,26,31). We therefore asked whether Bim also contributes to gzmB-mediated apoptosis in mice by incubating ex vivo mouse gzmB ϩ Tc cells with either WT or Bimdeficient 3T9 MEF cells (3T9 MEF.Bim Ϫ/Ϫ ).…”

Section: Resultsmentioning

confidence: 99%

Mouse Cytotoxic T Cell-derived Granzyme B Activates the Mitochondrial Cell Death Pathway in a Bim-dependent Fashion

Catalán

Jaime-Sánchez

Aguiló

et al. 2015

Journal of Biological Chemistry

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Background: Cytotoxic T cells employ perforin and granzyme B to kill tumor cells. Results: Bim-deficient 3T9-transformed MEF cells are resistant to gzmB-induced apoptosis. Conclusion:The mitochondrial apoptotic pathway activated via Bim is critically involved in apoptosis induced by mouse granzyme B. Significance: Learning how granzyme B induces apoptosis in different tumor cell types will help to predict and increase the efficacy of cancer immunotherapy.

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Mouse granzyme K has pro-inflammatory potential

Cited by 93 publications

References 45 publications

Effector Vγ9Vδ2 T cells dominate the human fetal γδ T-cell repertoire

Effector Vγ9Vδ2 T cells dominate the human fetal γδ T-cell repertoire

Mouse granzyme A induces a novel death with writhing morphology that is mechanistically distinct from granzyme B-induced apoptosis

Mouse Cytotoxic T Cell-derived Granzyme B Activates the Mitochondrial Cell Death Pathway in a Bim-dependent Fashion

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