Mucosa-associated microbiota drives pathogenic functions in IBD-derived intestinal iNKT cells

Burrello, Claudia; Pellegrino, Gabriella; Giuffrè, Maria Rita; Lovati, Giulia; Magagna, Ilaria; Bertocchi, Alice; Cribiù, Fulvia Milena; Boggio, Francesca; Botti, F.; Trombetta, Elena; Porretti, Laura; Sabatino, Antonio Di; Vecchi, Maurizio; Rescigno, María; Caprioli, Flavio; Facciotti, Federica

doi:10.26508/lsa.201800229

Cited by 30 publications

(31 citation statements)

References 80 publications

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“…On the contrary, Odoribacter spp. and Lactobacillus C30A , two SCFA-producers present at low levels in DSS-treated mice [19] and in IBD patients [14], showed a slight increase upon FMT (Figure 6E).…”

Section: Resultsmentioning

confidence: 99%

“…Here, the expansion of these beneficial taxa in FMT-treated mice, and the contraction of pro-inflammatory taxa, such as Proteobacteria , Enterobacteriaceae , Enterococcaceae , Christensenellaceae , and Streptococacceae [7,14], also suggested a shift in the metabolic functions of the microbial ecology. Indeed, Phylogenetic Investigation of Communities by Reconstruction of Unobserved States (PICRUSt) analyses predicted that the restoration of a normobiotic ecology is associated with increased tryptophan (Trp) and isoleucine/leucine metabolism.…”

Section: Discussionmentioning

confidence: 99%

“…Conventional CD4+ T helper (Th) cells have been shown to play key role in coordinating intestinal inflammatory responses [12,13], although other mucosal T cell populations. including Type 1 [14] and Type 2 Natural Killer T (NKT) cells [15,16], contribute to sustain intestinal inflammation. Conversely, regulatory T cell populations, such as Treg [17] and Tr1 cells [18], participate in the control of Th17-mediated pathogenic responses in IBD patients.…”

Section: Introductionmentioning

confidence: 99%

“…Therefore, besides the control of the disease, restoration of a normobiotic core intestinal ecology [14,19,20] is becoming a long-term therapeutic goal in various gastrointestinal disorders [21]. One widely explored option to manipulate and treat disorders associated with microbiota alterations is fecal microbiota transplantation (FMT), i.e., the infusion of a healthy donor feces in the intestine of an affected recipient.…”

Section: Introductionmentioning

confidence: 99%

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Fecal Microbiota Transplantation Controls Murine Chronic Intestinal Inflammation by Modulating Immune Cell Functions and Gut Microbiota Composition

Burrello

Giuffrè

Macandog

et al. 2019

Cells

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Different gastrointestinal disorders, including inflammatory bowel diseases (IBD), have been linked to alterations of the gut microbiota composition, namely dysbiosis. Fecal microbiota transplantation (FMT) is considered an encouraging therapeutic approach for ulcerative colitis patients, mostly as a consequence of normobiosis restoration. We recently showed that therapeutic effects of FMT during acute experimental colitis are linked to functional modulation of the mucosal immune system and of the gut microbiota composition. Here we analysed the effects of therapeutic FMT administration during chronic experimental colitis, a condition more similar to that of IBD patients, on immune-mediated mucosal inflammatory pathways. Mucus and feces from normobiotic donors were orally administered to mice with established chronic Dextran Sodium Sulphate (DSS)-induced colitis. Immunophenotypes and functions of infiltrating colonic immune cells were evaluated by cytofluorimetric analysis. Compositional differences in the intestinal microbiome were analyzed by 16S rRNA sequencing. Therapeutic FMT in mice undergoing chronic intestinal inflammation was capable to decrease colonic inflammation by modulating the expression of pro-inflammatory genes, antimicrobial peptides, and mucins. Innate and adaptive mucosal immune cells manifested a reduced pro-inflammatory profile in FMT-treated mice. Finally, restoration of a normobiotic core ecology contributed to the resolution of inflammation. Thus, FMT is capable of controlling chronic intestinal experimental colitis by inducing a concerted activation of anti-inflammatory immune pathways, mechanistically supporting the positive results of FMT treatment reported in ulcerative colitis patients.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Fecal Microbiota Transplantation Controls Murine Chronic Intestinal Inflammation by Modulating Immune Cell Functions and Gut Microbiota Composition

Burrello

Giuffrè

Macandog

et al. 2019

Cells

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“…While the key role of NKT cells in Th2‐driven models of colitis—such as oxazolone—is well established, their functions in CD and CD‐like mouse models remain controversial. In humans, iNKT cells from the lamina propria of CD patients produce pro‐inflammatory TNF‐α, IFN‐γ, IL‐17A and IL‐13 and can disrupt epithelial monolayer integrity, suggesting that they could contribute to disease pathology . In the DSS model of IBD, NKTs have been shown to be protective in some studies but have no effect in some others.…”

Section: Nkt Cells In the Intestinal Compartmentmentioning

confidence: 99%

NKT cells and the regulation of intestinal immunity: a two‐way street

2020

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The mammalian gastrointestinal compartment is colonised by millions of microorganisms that have a central influence on human health. Intestinal homeostasis requires a continuous dialogue between the commensal bacteria and intestinal immune cells. While interactions between host and commensal bacteria are normally beneficial, allowing training and functional tuning of immune cells, dysregulated immune system-microbiota crosstalk can favour the development of chronic inflammatory diseases, as it is the case for inflammatory bowel disease (IBD). Natural killer T (NKT) cells, which recognise CD1-restricted microbial and self-lipids, contribute to the regulation of mucosal immunity by controlling intestinal homeostasis and participating in the development of IBD. Here, we provide an overview of the recently identified pathways underlying the crosstalk between commensal bacteria and NKT cells and discuss the effect of these interactions in intestinal health and disease.

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Human intestinal and circulating invariant natural killer T cells are cytotoxic against colorectal cancer cells via the perforin–granzyme pathway

et al. 2021

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Invariant natural killer T (iNKT) cells are lipid-specific T lymphocytes endowed with cytotoxic activities and are thus considered important in antitumor immunity. While several studies have demonstrated iNKT cell cytotoxicity against different tumors, very little is known about their cellkilling activities in human colorectal cancer (CRC). Our aim was to assess whether human iNKT cells are cytotoxic against colon cancer cells and the mechanisms underlying this activity. For this purpose, we generated stable iNKT cell lines from peripheral blood and colon specimens and used NK-92 and peripheral blood natural killer cells as cell-mediated cytotoxicity controls. In vitro cytotoxicity was assessed using a panel of well-characterized human CRC cell lines, and the cellular requirements for iNKT cell cytotoxic functions were evaluated. We demonstrated that both intestinal and circulating iNKT cells were cytotoxic against the entire panel of CRC lines, as well as against freshly isolated patient-derived colonic epithelial cancer cells. Perforin and/or granzyme inhibition impaired iNKT cell cytotoxicity, whereas T-cell receptor (TCR) signaling was a less stringent requirement for efficient killing. This study is the first evidence of tissue-derived iNKT cell cytotoxic activity in humans, as it shows that iNKT cells depend on the perforin-granzyme pathway and both adaptive and innate signal recognition for proper elimination of colon cancer cells.

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Mucosa-associated microbiota drives pathogenic functions in IBD-derived intestinal iNKT cells

Abstract: Pro-inflammatory iNKT cells are enriched in IBD patients’ lamina propria. Exposure to the mucosa-associated microbiota drives their activation, inducing pathogenic activities against the epithelium.

Cited by 30 publications

References 80 publications

Fecal Microbiota Transplantation Controls Murine Chronic Intestinal Inflammation by Modulating Immune Cell Functions and Gut Microbiota Composition

Fecal Microbiota Transplantation Controls Murine Chronic Intestinal Inflammation by Modulating Immune Cell Functions and Gut Microbiota Composition

NKT cells and the regulation of intestinal immunity: a two‐way street

Human intestinal and circulating invariant natural killer T cells are cytotoxic against colorectal cancer cells via the perforin–granzyme pathway

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