Effective Barriers: The Role of NKT Cells and Innate Lymphoid Cells in the Gut

Cairo, Cristiana; Webb, Tonya J.

doi:10.4049/jimmunol.2100799

Cited by 8 publications

(7 citation statements)

References 216 publications

(217 reference statements)

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“…2d and 2e) showed a reduction in almost all LP CD4 + T cell populations in KD-fed mice. Only LP natural killer T cells and type 3 innate lymphoid cells (GF LP) were increased – both have been associated to gut homeostasis and health 10 . Finally, the expression of both subunits of calprotectin (a biomarker of inflammation used in inflammatory bowel disease 11 ) was reduced in the spleens of GF KD-fed mice (Extended Data Fig.…”

Section: Resultsmentioning

confidence: 99%

The gut microbiome-linked long chain fatty acid stearate suppresses colorectal cancer

Tsenkova,

Brauer,

Pozdeev

et al. 2023

Preprint

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Colorectal cancer (CRC) patients have been shown to possess an altered gut microbiome. Diet is a known microbiome modulator. An attenuating effect of the ketogenic diet (KD) on CRC cell growth has been previously observed, however the role of the gut microbiome in driving this effect remains unknown. Here, we describe a reduced colonic tumor burden upon KD consumption in a CRC mouse model with a humanized microbiome. Importantly, we demonstrate a causal relationship through microbiome transplantation into germ-free mice, whereby alterations in gut microbial function were maintained in the absence of continued selective pressure from the KD. Stearic acid is identified as a putative microbiome-derived anti-cancer metabolite. Taken together, the beneficial effects of the KD are mediated by the gut microbiome and may be dependent on a pre-existing “non-responder” or “responder” gut microbiome profile. These results have important implications for future clinical trials evaluating the effects of the ketogenic diet on human CRC.

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Section: Resultsmentioning

confidence: 99%

The gut microbiome-linked long chain fatty acid stearate suppresses colorectal cancer

Tsenkova,

Brauer,

Pozdeev

et al. 2023

Preprint

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“…The functional activity of NKT cells is realized through effector (perforin/granzyme and/or FasLmediated) mechanisms and regulatory (cytokine production) providing the relationship between innate and adaptive immunity [6,12,40]. The subset composition of NKT cells is determined by CD16 and CD56 receptor expression.…”

Section: Discussionmentioning

confidence: 99%

“…Accordingly, the functional activity of NKT cells is realized in various mechanisms of the immune response, realizing the relationship between natural resistance and adaptive immunity. This lymphocyte subset is involved in the mechanisms of antiviral and antiparasitic protection, and also secreted different immunoregulatory cytokines in the site of inflammation [1,10,12]. In addition, NKT cells are able to stimulate and inhibit antitumor immune responses [9,39].…”

Section: Introductionmentioning

confidence: 99%

Disseminated purulent peritonitis outcome affects NKT cell phenotype

Савченко

Борисов

Kudryavtsev

et al. 2022

Russian Journal of Infection and Immunity

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The aim of our study was to investigate the main characteristics of peripheral blood NKT cell phenotype in patients with disseminated purulent peritonitis (DPP) in dynamics of postoperative period, depending on the disease outcome. Fifty-two patients with acute surgical diseases and injuries of the abdominal organs complicated by DPP, and 68 healthy individuals in control group, were examined. Blood sampling was performed before surgery (preoperative period), as well as on the day 7, 14 and 21 of postoperative period. All patients with DPP were divided into two groups depending on disease outcome in postoperative period: patients with favorable disease outcome (n = 34); and patients with unfavorable outcome (n = 18). Study of the phenotype of blood NKT lymphocytes was performed by flow cytometry using direct immunofluorescence of whole peripheral blood samples with monoclonal antibodies. The low relative and absolute level of NKT cells was observed in DPP patients regardless of outcome disease in preoperative period. At the same time, the absolute level of NKT cells returned to normal only in patients with favorable DPP outcome and only by day 21 after surgery. Patients with favorable DPP outcome by the end of examination period had normalized quantity of mature NKT-lymphocytes and significantly decreased level of cytotoxic cells which was apparently associated with migration of such cell subsets to site of inflammation. A reduced level of non-classical (expressing CD8 marker) mature and cytokine-producing NKT cells was detected only in patients with favorable DPP outcome in preoperative period which returned to normal by the end of postoperative period. At the same time, patients with unfavorable disease outcome had reduced quantity of NKT cells of these subsets by day 21 of postoperative treatment. Patients with favorable outcome had high level of mature and cytotoxic CD11b+ NKT cells already in the preoperative period, while patients with unfavorable DPP outcome had increased level of cytotoxic CD11b+ NKT cells only by day 21 after surgery. The proportion of NKT cells expressing activation markers (CD28 and CD57) was reduced in patients in preoperative period that returned to normal immediately after surgery with favorable outcome, while it recovered with unfavorable outcome closer to the end of postoperative examination. The defined features of NKT cell phenotype in patients with unfavorable DPP outcome characterize disturbances in subset ratio and mechanisms of functioning of this cell fraction. This determines a need to develop immunotherapeutic methods aimed at stimulating immunoregulatory activity of NKT cells.

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“…Interestingly, we did not observe significant overlap of these two pathways in the 8 mononuclear phagocytic populations (Figure 6C). However, when we performed RNA velocity analysis that imputes cell fates (53,54,61,(84)(85)(86)(87)(88), we identified a robust directional flow from the efferocytosis high C1QC + macrophages towards the inflammasome rich NLRP3 + subset through an intermediate ISG15 + macrophage state (Figure 6E, Supplementary Figure S4, Supplementary Tables S6). We observed that another efferocytosis-rich cluster, SPP1 + , can also develop into the NLRP3 + macrophage subset (Figure 6E).…”

Section: Efferocytosis Induces Il1b Signature In Macrophagesmentioning

confidence: 99%

Efferocytosis drives myeloid NLRP3 dependent inflammasome signaling secretion of IL-1β to promote tumor growth

et al. 2022

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Caspase-1 signaling in myeloid suppressor cells can promote T-cell independent cancer progression, but the regulation of inflammasome signaling within the highly heterogeneous myeloid population in the tumor milieu remains elusive. To resolve this complexity, single cell transcriptomic profile of Head and Neck Squamous Cell Carcinoma (HNSCC) identified distinct inflammasome-associated genes within specific clusters of tumor-infiltrating myeloid cells. Among these myeloid cells, the sensor protein, NLRP3, and downstream effector IL-1β transcripts were enriched in discreet monocytic and macrophage subtypes in the TME. We showed that deletion of NLRP3, but not AIM2, phenocopied caspase-1/IL-1β dependent tumor progression in vivo. Paradoxically, we found myeloid-intrinsic caspase-1 signaling increased myeloid survival contrary to what would be predicted from the canonical pyroptotic function of caspase-1. This myeloid NLRP3/IL-1β signaling axis promotion of tumor growth was found to be gasdermin D independent. Mechanistically, we found that phagocyte-mediated efferocytosis of dying tumor cells in the TME directly activated NLRP3-dependent inflammasome signaling to drive IL-1β secretion. Subsequently we showed that NLRP3-mediated IL-1β production drives tumor growth in vivo. Dynamic RNA velocity analysis showed a robust directional flow from efferocytosis gene-set high macrophages to an inflammasome gene-set high macrophage population. We provide a novel efferocytosis-dependent inflammasome signaling pathway which mediates homeostatic tumor cell apoptosis that characterizes chronic inflammation-induced malignancy.

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Effective Barriers: The Role of NKT Cells and Innate Lymphoid Cells in the Gut

Cited by 8 publications

References 216 publications

The gut microbiome-linked long chain fatty acid stearate suppresses colorectal cancer

The gut microbiome-linked long chain fatty acid stearate suppresses colorectal cancer

Disseminated purulent peritonitis outcome affects NKT cell phenotype

Efferocytosis drives myeloid NLRP3 dependent inflammasome signaling secretion of IL-1β to promote tumor growth

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