IL-10 signaling in dendritic cells controls IL-1β-mediated IFNγ secretion by human CD4+ T cells: relevance to inflammatory bowel disease

Veenbergen, Sharon; Li, Peiyao; Raatgeep, H. C.; Lindenbergh-Kortleve, Dicky J.; Simons-Oosterhuis, Ytje; Farrel, Alvin; Costes, L M M; Joosse, Maria E.; Berkel, Lisette A. van; Ruiter, Lilian F. de; Leeuwen, M.A. van; Winter, Deborah R.; Holland, Steven M.; Freeman, AF; Wakabayashi, Yu; Zhu, Jinfang; Ridder, Lissy de; Driessen, G. J.; Escher, Johanna C.; Leonard, Warren J.; Samsom, Janneke N.

doi:10.1038/s41385-019-0194-9

Cited by 50 publications

(36 citation statements)

References 50 publications

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“…Likewise in humans, Bt OMVs could elicit immunomodulatory functions via different mechanisms in addition to their role in directing balanced DC responses that could change in inflammatory settings such as in IBD. A recent study has demonstrated a key role for IL-10R signalling in DC in controlling aberrant Th1 responses both via inhibition of IL-1b and IL-12 in paediatric IBD and in an individual with IL10RA gene deficiency 70 . This fits with previous reports that IL-10 is both produced by and acts via DC to regulate intestinal inflammation 42 .…”

Section: Discussionmentioning

confidence: 99%

“…For instance, Bt has been shown to elicit IL-8 from paediatric CD biopsies but not from healthy controls 73 . Additionally, reduced IL10RA expression and reduced responsiveness occur in a subgroup of more severe paediatric IBD patients and these are associated with enhanced IL-1b expression 70 . It will in future studies be important to identify the specific factor or factors present in Bt OMVs that trigger a healthy immune response to realise their potential use as a novel therapy for IBD.…”

Section: Discussionmentioning

confidence: 99%

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Bacteroides thetaiotaomicron-derived outer membrane vesicles promote regulatory dendritic cell responses in health but not in inflammatory bowel disease

Durant

Stentz

Noble

et al. 2020

Preprint

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Background: Bacteroides thetaiotaomicron (Bt) is a prominent member of the human intestinal microbiota that, like all Gram-negative bacteria, naturally generates nanosized outer membrane vesicles (OMVs) which bud off from the cell surface. Importantly, OMVs can cross the intestinal epithelial barrier to mediate microbe-host cell crosstalk involving both epithelial and immune cells to help maintain intestinal homeostasis. Here we have examined the interaction between Bt OMVs and blood or colonic mucosa-derived dendritic cells (DC) from healthy individuals and patients with Crohn’s disease (CD) or ulcerative colitis (UC). Results: In healthy individuals, Bt OMVs stimulated significant (p<0.05) IL-10 expression by colonic DC, whereas in peripheral blood-derived DC they also stimulated significant (p<0.001 and p<0.01, respectively) expression of IL-6 and the activation marker CD80. Conversely, in UC Bt OMVs were unable to elicit IL-10 expression by colonic DC. There were also reduced numbers of CD103+ DC in the colon of both UC and CD patients compared to controls, supporting a loss of regulatory DC in both diseases. Furthermore, in CD and UC, Bt OMVs elicited a significantly lower proportion of DC which expressed IL-10 (p<0.01 and p<0.001, respectively) in blood compared to controls. These alterations in DC responses to Bt OMVs were seen in patients with inactive disease, and thus are indicative of intrinsic defects in immune responses to this commensal in inflammatory bowel disease (IBD). Conclusions: Overall, our findings suggest a key role for OMVs generated by the commensal gut bacterium Bt in directing a balanced immune response to constituents of the microbiota locally and systemically during health which is altered in IBD patients.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Bacteroides thetaiotaomicron-derived outer membrane vesicles promote regulatory dendritic cell responses in health but not in inflammatory bowel disease

Durant

Stentz

Noble

et al. 2020

Preprint

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“…Patients with rare deleterious mutations in the IL10 axis develop a unique infantile-onset form of IBD. As such, we and others have previously characterized various dysregulated immune responses in these patients in both innate and adaptive immunity (10,12,(32)(33)(34)(35)(36). We were able to show that loss of IL10 signaling does not impair the suppressive capacity of Tregs, but leads to enhanced generation of T H 17 cells and upregulation of IL1mediated responses (13).…”

Section: Discussionmentioning

confidence: 67%

Alterations in T and B Cell Receptor Repertoires Patterns in Patients With IL10 Signaling Defects and History of Infantile-Onset IBD

et al. 2020

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Patients with loss-of-function mutations in IL10 or IL10 receptor (IL10R) genes develop severe, medical-refractory, infantile-onset inflammatory bowel disease (IBD). We have previously reported significant alterations in innate and adaptive immune responses in these patients. Next generation sequencing platforms enable a comprehensive assessment of T cell receptor (TCR) and B cell receptor (BCR) repertoire patterns. We aimed to characterize TCR and BCR features in peripheral blood of patients with deleterious IL10 signaling defects. DNA was isolated from blood of seven patients with IL10R mutations and one with an IL10 mutation, along with eight controls, and subjected to next generation sequencing of TRB and IgH loci. A significant increase in clonality was observed in both TCR and BCR repertoires in circulating lymphocytes of IL10/IL10R-deficient patients, but to a much greater extent in T cells. Furthermore, short CDR3β length and altered hydrophobicity were demonstrated in T cells of patients, but not in B cells, secondary to lower rates of insertions of nucleotides, but not deletions, at the V-, D-, or J-junctions. We were unable to observe specific T or B clones that were limited only to the patients or among controls. Moreover, the expanded T cells clones were unique to each patient. In conclusion, next generation sequencing of the TCR and BCR is a powerful tool for characterizing the adaptive immune cell phenotype and function in immune-mediated disorders. The oligoclonality observed among IL10/IL10R-deficient patients may suggest specialization of unique clones that

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“…However, it is also possible that inflammation is associated with down-regulation of the IL-10 receptor on targets cells. Our lab has recently shown that reduced IL10RA expression was detected in peripheral blood mononuclear cells of therapy-naïve pediatric IBD patients [254]. In agreement, a proof of concept experiment showed that IL-10 responsiveness is heterogeneous among IBD patients [254].…”

Section: Does Adoptive Transfer Of Tr1 Cells Attenuate Disease?mentioning

confidence: 59%

“…Our lab has recently shown that reduced IL10RA expression was detected in peripheral blood mononuclear cells of therapy-naïve pediatric IBD patients [254]. In agreement, a proof of concept experiment showed that IL-10 responsiveness is heterogeneous among IBD patients [254]. Patients that were less sensitive to the IL-10 inhibitory effects exhibited clinical and immunological differences at time of diagnosis.…”

Section: Does Adoptive Transfer Of Tr1 Cells Attenuate Disease?mentioning

confidence: 63%

Dissecting the Heterogeneity in T-Cell Mediated Inflammation in IBD

Tindemans

Joosse

Samsom

2020

Cells

111

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Infiltration of the lamina propria by inflammatory CD4+ T-cell populations is a key characteristic of chronic intestinal inflammation. Memory-phenotype CD4+ T-cell frequencies are increased in inflamed intestinal tissue of IBD patients compared to tissue of healthy controls and are associated with disease flares and a more complicated disease course. Therefore, a tightly controlled balance between regulatory and inflammatory CD4+ T-cell populations is crucial to prevent uncontrolled CD4+ T-cell responses and subsequent intestinal tissue damage. While at steady state, T-cells display mainly a regulatory phenotype, increased in Th1, Th2, Th9, Th17, and Th17.1 responses, and reduced Treg and Tr1 responses have all been suggested to play a role in IBD pathophysiology. However, it is highly unlikely that all these responses are altered in each individual patient. With the rapidly expanding plethora of therapeutic options to inhibit inflammatory T-cell responses and stimulate regulatory T-cell responses, a crucial need is emerging for a robust set of immunological assays to predict and monitor therapeutic success at an individual level. Consequently, it is crucial to differentiate dominant inflammatory and regulatory CD4+ T helper responses in patients and relate these to disease course and therapy response. In this review, we provide an overview of how intestinal CD4+ T-cell responses arise, discuss the main phenotypes of CD4+ T helper responses, and review how they are implicated in IBD.

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IL-10 signaling in dendritic cells controls IL-1β-mediated IFNγ secretion by human CD4+ T cells: relevance to inflammatory bowel disease

Cited by 50 publications

References 50 publications

Bacteroides thetaiotaomicron-derived outer membrane vesicles promote regulatory dendritic cell responses in health but not in inflammatory bowel disease

Bacteroides thetaiotaomicron-derived outer membrane vesicles promote regulatory dendritic cell responses in health but not in inflammatory bowel disease

Alterations in T and B Cell Receptor Repertoires Patterns in Patients With IL10 Signaling Defects and History of Infantile-Onset IBD

Dissecting the Heterogeneity in T-Cell Mediated Inflammation in IBD

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