Granzymes A and K differentially potentiate LPS-induced cytokine response

Wensink, Annette C.; Kok, Helena M.; Meeldijk, Jan; Fermie, Job; Froelich, Christopher J.; Hack, C. E.; Bovenschen, Niels

doi:10.1038/cddiscovery.2016.84

Cited by 24 publications

(38 citation statements)

References 43 publications

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“…Additionally, intestinal GrA + Th cells in aGVHD mice did not express perforin (data not shown). GrA has other reported roles in promoting inflammatory cytokine and chemokine production (IL-1β, IL-6, TNF, MCP-1) via interaction with TLRs ( 42 – 45 ). However, these cytokines were not differentially expressed within the intestines, and only MCP-1 was significantly reduced in the serum of Gzma –/– recipient mice.…”

Section: Discussionmentioning

confidence: 99%

Granzyme A–producing T helper cells are critical for acute graft-versus-host disease

et al. 2020

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Intestinal GrA + Th cells in aGVHD represent a distinct Th lineage. Although the cellular sources were not defined, enhanced Gzma expression was previously observed in the intestines during aGVHD but only minimally in the skin and lymphoid organs (11). At 10 days post-HCT, we observed significantly increased expression of Gzma in both the small intestine (SI) and large intestine (LI) of mice that received allogeneic bone marrow and T cells as compared with syngeneic controls (P = 0.01 and P < 0.0001, respectively, Figure 1A). We observed a population of GrA + CD8 + T cells in all organs examined in allogeneic recipients that was present in lower percentages in syngeneic recipients (Figure 1, B and C). Unexpectedly, CD4 + T cells also produced GrA in allogeneic recipients and were the dominant population of GrA-producing T cells within the small and large intestines, the latter being where CD4 + T cells accounted for approximately 75% of the GrA-producing cells (Figure 1, B-D). A limited proportion of intestinal GrA + Th cells coexpressed GrB in the SI or LI, indicating that these cells did not acquire a classic cytotoxic phenotype (Figure 1E) (12-15). GrA + cells did not coexpress FOXP3 or IL-17A (Figure 1E) but exhibited partial coexpression of IFN-γ, which was slightly more pronounced in the LI versus the SI (~40% vs. ~30%, Figure 1E). To determine if GrA + Th cells were related to IFN-γ-producing Th1 cells, we analyzed lineage-specific cytokine and transcription factor expression (Supplemental Table 2; supplemental material available online with this article; https://doi.org/10.1172/ jci.insight.124465DS1) within intestinal CD3 + CD4 + T cells using time-of-flight cytometry (CyTOF). GrA + Th cells were spatially clustered, indicating that GrA expression is limited to a distinct population of Th cells and is not shared by multiple Th subsets (Figure 1F). In contrast, IFN-γ + Th cells were distributed between 2 major populations, those that spatially segregated with TNF + IL-2 + cells (i.e., prototypic Th1 cells) and those that partially overlapped with GrA + Th cells (Figure 1F). Cells that expressed high levels of GrA exhibited minimal overlap with other lineage-specific cytokines, many of which were expressed in low amounts (Supplemental Figure 1). These data indicate that GrA + Th cells are not typical Th1 cells and may represent a novel Th cell type that responds to signals involved with intestinal damage or inflammation. GrA is expressed by human Th cells in a PBMC-induced model of GVHD. Our data indicate that CD4 + Th cells are an important source of GrA and thus may be relevant to human GVHD. To examine this further, we adopted an established model (16) of human PBMC-induced GVHD in immune-compromised NRG mice. Briefly, human PBMCs from 2 individual donors were injected into NRG mice, and mice were monitored until they reached 20% body weight loss or a significant clinical score (>3). At this endpoint, mice were euthanized, and immune cells were isolated from the spleen, liver, SI, and LI and analyzed fo...

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Section: Discussionmentioning

confidence: 99%

Granzyme A–producing T helper cells are critical for acute graft-versus-host disease

et al. 2020

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“…In mice, granzyme M synergistically enhances the inflammatory response to LPS challenging , and furthermore promotes secretion of MIP‐1a from NK cells . Interestingly, also highly expressed granzymes A and K have recently be described to show strong proinflammatory effects in reaction to bacterial stimuli . Thus, granzyme M is the third rather proinflammatory granzyme with anti‐bacterial properties that is highly expressed in MAIT cells.…”

Section: Discussionmentioning

confidence: 99%

Proteomic definition of human mucosal‐associated invariant T cells determines their unique molecular effector phenotype

et al. 2018

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Mucosal-associated invariant T cells (MAIT) constitute the most abundant anti-bacterial CD8 T-cell population in humans. MR1/TCR-activated MAIT cells were reported to organize cytotoxic and innate-like responses but knowledge about their molecular effector phenotype is still fragmentary. Here, we have examined the functional inventory of human MAIT cells (CD3 Vα7.2 CD161 ) in comparison with those from conventional non-MAIT CD8 T cells (cCD8 ) and NK cells. Quantitative mass spectrometry characterized 5500 proteins of primary MAIT cells and identified 160 and 135 proteins that discriminate them from cCD8 T cells and NK cells donor-independently. Most notably, MAIT cells showed a unique exocytosis machinery in parallel to a proinflammatory granzyme profile with high levels of the granzymes A, K, and M. Furthermore, 24 proteins were identified with highest abundances in MAIT cells, including CD26, CD98, and L-amino-oxidase (LAAO). Among those, expression of granzyme K and CD98 were validated as MAIT-specific with respect to non-MAIT CD8 effector subsets and LAAO was found to be recruited together with granzymes, perforin, and CD107a at the immunological synapse of activated MAIT cells. In conclusion, this study complements knowledge on the molecular effector phenotype of MAIT cells and suggest novel immune regulatory functions as part of their cytotoxic responses.

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“…GzmA promotes proinflammatory cytokine production including in the context of infectious diseases and rheumatoid arthritis (33, 36, 43, 44). In fact, various proinflammatory cytokines, such as IL-1β, TNF-α, IL-6, and IL-8 are induced by GzmA stimulation from LPS pre-sensitized macrophages in a TLR4-dependent manner or from monocytes treated with TLR2/TLR4 ligands (43–45). However, the effect of GzmA on DCs remains to be determined.…”

Section: Introductionmentioning

confidence: 99%

Granzyme A Stimulates pDCs to Promote Adaptive Immunity via Induction of Type I IFN

et al. 2019

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Granzyme A (GzmA), together with perforin, are well-known for their cytotoxic activity against tumor or virus-infected cells. In addition to this cytotoxic function, GzmA stimulates several immune cell types and induces inflammation in the absence of perforin, however, its effect on the dendritic cell (DC) is unknown. In the current study, we showed that recombinant GzmA induced the phenotypic maturation of plasmacytoid DCs (pDCs) and conventional DCs (cDCs), but not their apoptosis. Particularly, GzmA made pDCs more functional, thus leading to production of type I interferon (IFN) via the TLR9-MyD88 pathway. We also demonstrated that GzmA binds TLR9 and co-localizes with it in endosomes. When co-administered with antigen, GzmA acted as a powerful adjuvant for eliciting antigen-specific cytotoxic CD8 + T lymphocytes (CTLs) that protected mice from tumor challenge. The induction of CTL was completely abolished in XCR1 + DC-depleted mice, whereas it was reduced to less than half in pDC-depleted or IFN-α/β receptor knockout mice. Thus, CTL cross-priming was dependent on XCR1 + cDC and also type I IFN, which was produced by GzmA-activated pDCs. These results indicate that GzmA -stimulated pDCs enhance the cross-priming activity of cDCs in situ . We also showed that the adjuvant effect of GzmA is superior to CpG-ODN and LPS. Our findings highlight the ability of GzmA to bridge innate and adaptive immune responses via pDC help and suggest that GzmA may be useful as a vaccine adjuvant.

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Granzymes A and K differentially potentiate LPS-induced cytokine response

Cited by 24 publications

References 43 publications

Granzyme A–producing T helper cells are critical for acute graft-versus-host disease

Granzyme A–producing T helper cells are critical for acute graft-versus-host disease

Proteomic definition of human mucosal‐associated invariant T cells determines their unique molecular effector phenotype

Granzyme A Stimulates pDCs to Promote Adaptive Immunity via Induction of Type I IFN

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