A conserved Bacteroidetes antigen induces anti-inflammatory intestinal T lymphocytes

Bousbaine, Djenet; Fisch, Laura; London, Mariya; Bhagchandani, Preksha; Castro, Tiago B. R.; Mimee, Mark; Olesen, Scott W.; Reis, Bernardo Sgarbi; VanInsberghe, David; Bortolatto, Juliana; Poyet, Mathilde; Cheloha, Ross W.; Sidney, John; Ling, Jingjing; Gupta, Aaron; Lu, Timothy K.; Sette, Alessandro; Alm, Eric J.; Moon, James J.; Victora, Gabriel D.; Mucida, Daniel; Ploegh, Hidde L.; Bilate, Angelina M.

doi:10.1126/science.abg5645

Cited by 54 publications

(28 citation statements)

References 59 publications

(68 reference statements)

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“…3e, f ). To assess the intrinsic ability of OVA-presenting biotin + DCs to induce pTregs in a non-OT-II system, independently of the presence of antigen acquired in vivo , we performed co-culture experiments using monoclonal transnuclear (TN) T cells bearing an unrelated T cell receptor (TCR) specific for a peptide of the β-hexosaminidase enzyme of commensals of the Bacteroidetes phylum 27 . We co-cultured biotin + and biotin − DCs, labeled by the OT-II T cells in vivo , with naïve CD4 + TN T cells in the presence of the TN cognate peptide.…”

Section: Resultsmentioning

confidence: 99%

“…Cells were incubated at 37°C, 5% CO2 for 96 h. To determine the number of proliferated cells, all cells in each well were recorded by FACS and gated based on CFSE staining. For all other co-culture experiments, 1 μM of OT-II peptide (chicken OVA amino acids 323-339 - Anaspec AS-27024) or TN peptide (β-hex peptide sequence YKGSRVWLN - GenScript) 27 was added to the wells. 50 Biotin − or Biotin + DCs and 750 naïve CD4 + OT-II or TN CFSE-labeled T cells from the spleen were sorted into U bottom 96well plate containing supplemented RPMI and 2% of T-stim media.…”

Section: Methodsmentioning

confidence: 99%

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Identification of dendritic cell-T cell interactions driving immune responses to food

Canesso

Castro

Nakandakari-Higa

et al. 2022

Preprint

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The intestinal immune system must concomitantly tolerate food and commensals and protect against pathogens. Dendritic cells (DCs) orchestrate these immune responses by presenting luminal antigens and inducing functional differentiation of CD4+ T cells into regulatory (pTreg) or pro-inflammatory (Th) subsets. However, the exact nature of the DCs inducing tolerance or inflammation to dietary antigens has been difficult to define. Using an intestine-adapted Labeling Immune Partnerships by SorTagging Intercellular Contacts (LIPSTIC) combined with single-cell transcriptomics, we characterized DCs presenting dietary antigens in the context of tolerance or infection. At steady-state, migratory cDC1 and cDC2 DCs, but not resident DCs, were found to present dietary antigen to cognate CD4+ T cells. Whereas cDC2s promoted T cell activation, only cDC1s induced their differentiation into pTregs. Infection with the helminth Strongyloides venezuelensis abrogated cDC1 presentation of dietary antigens, preventing pTreg and oral tolerance induction. In contrast, Heligmosomoides polygyrus infection only partially affected cDC1s, allowing oral tolerance to be maintained. An expanded population of cDC2s that induced type-2 immunity during both helminth infections did not present dietary antigens, demonstrating that compartmentalized presentation of luminal antigens can prevent food-specific Th2 responses during inflammatory conditions. Our data uncover novel cellular mechanisms by which tolerance to food is induced and can be disrupted during infections.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Identification of dendritic cell-T cell interactions driving immune responses to food

Canesso

Castro

Nakandakari-Higa

et al. 2022

Preprint

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“…A conserved commensal antigen, β-hexosaminidase (HEXA_B), has a major role in induction of anti-inflammatory intestinal T lymphocytes 43 , and is present in 59 of our isolates with enrichment in Prevotella, Streptococcus and Pauljensenia spp.…”

Section: Resultsmentioning

confidence: 99%

Genomic and ecologic characteristics of the airway microbial-mucosal complex

Cuthbertson

Löber

Ish-Horowicz

et al. 2022

Preprint

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Lung diseases due to infection and dysbiosis affect hundreds of millions of people world-wide. Microbial communities at the airway mucosal barrier are conserved and highly ordered, reflecting symbiosis and co-evolution with human host factors. Freed of selection to digest nutrients for the host, the airway microbiome underpins cognate management of mucosal immunity and pathogen resistance. We show here the results of the first systematic culture and whole-genome sequencing of the principal airway bacterial species, identifying abundant novel organisms within the genera Streptococcus, Pauljensenia, Neisseria and Gemella. Bacterial genomes were enriched for genes encoding antimicrobial synthesis, adhesion and biofilm formation, immune modulation, iron utilisation, nitrous oxide (NO) metabolism and sphingolipid signalling. RNA-targeting CRISPR elements in some taxa suggest the potential to prevent or treat specific viral infections. Homologues of human RO60 present in Neisseria spp. provide a possible respiratory primer for autoimmunity in systemic lupus erythematosus (SLE) and Sjogren syndrome. We interpret the structure and biogeography of airway microbial communities from clinical surveys in the context of whole-genome content, identifying features of airway dysbiosis that may presage breakdown of homeostasis during acute attacks of asthma and chronic obstructive pulmonary disease (COPD). We match the gene content of isolates to human transcripts and metabolites expressed late in airway epithelial differentiation, identifying pathways that can sustain host interactions with the microbiota. Our results provide a systematic basis for decrypting interactions between commensals, pathogens, and mucosal immunity in lung diseases of global significance.

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“…Remarkably, even though various human gut microbes, especially commensals, promoting colonic FoxP3 + Treg differentiation in mice have been identified (39)(40)(41)(42)(43), to our knowledge, direct evidences regarding the presence of Tregs specific for these bacteria in the human colonic mucosa, either FoxP3 + or Tr1-like, are still lacking. Nonetheless, the presence of commensal-specific T cells has been shown, among both circulating CD4 + effectors T cells (44) and CD4 + /CD8aa + regulatory intra-epithelial lymphocytes in the small intestine (45), both populations being key in human gut barrier integrity maintenance.…”

Section: Discussionmentioning

confidence: 99%

Human gut microbiota-reactive DP8α regulatory T cells, signature and related emerging functions

Jotereau

Alameddine²,

Teusan³

et al. 2022

Front. Immunol.

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In mice, microbiota-induced Tregs both maintain intestinal homeostasis and provide resistance to immuno-pathologies in the adult. Identifying their human functional counterpart therefore represents an important goal. We discovered, in the human colonic lamina propria and blood, a FoxP3-negative IL-10-secreting Treg subset, which co-expresses CD4 and CD8α (hence named DP8α) and displays a TCR-reactivity against Faecalibacterium prausnitzii, indicating a role for this symbiotic bacterium in their induction. Moreover, supporting their role in intestinal homeostasis, we previously reported both their drastic decrease in IBD patients and their protective role in vivo against intestinal inflammation, in mice. Here, we aimed at identifying the genomic, phenotypic and functional signatures of these microbiota-induced Tregs, towards delineating their physiological role(s) and clinical potential. Human F. prausnitzii-reactive DP8α Treg clones were derived from both the colonic lamina propria and blood. RNA-sequencing, flow cytometry and functional assays were performed to characterize their response upon activation and compare them to donor- and tissue-matched FoxP3+ Treg clones. DP8α Tregs exhibited a unique mixed Tr1-like/cytotoxic CD4+ T cell-profile and shared the RORγt and MAF master genes with mouse gut microbiota-induced FoxP3+ Tregs. We revealed their potent cytotoxic, chemotactic and IgA-promoting abilities, which were confirmed using in vitro assays. Therefore, besides their induction by a Clostridium bacterium, DP8α Tregs also partake master genes with mouse microbiota-induced Tregs. The present identification of their complete signature and novel functional properties, should be key in delineating the in vivo roles and therapeutic applications of these unique human microbiota-induced Tregs through their study in pathological contexts, particularly in inflammatory bowel diseases.

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A conserved Bacteroidetes antigen induces anti-inflammatory intestinal T lymphocytes

Cited by 54 publications

References 59 publications

Identification of dendritic cell-T cell interactions driving immune responses to food

Identification of dendritic cell-T cell interactions driving immune responses to food

Genomic and ecologic characteristics of the airway microbial-mucosal complex

Human gut microbiota-reactive DP8α regulatory T cells, signature and related emerging functions

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