The CD4+ T cell response to a commensal-derived epitope transitions from a tolerant to an inflammatory state in Crohn’s disease

Pedersen, Thomas Klit; Brown, Eric; Plichta, Damian R.; Johansen, Joachim; Twardus, Shaina W.; Delorey, Toni; Lau, Helena; Vlamakis, Hera; Moon, James J.; Xavier, Ramnik J.; Graham, Daniel B.

doi:10.1016/j.immuni.2022.08.016

Cited by 25 publications

(18 citation statements)

References 90 publications

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“…Importantly, loss of epithelial expression of HDAC3 or MHCII resulted in reduced commensal-specific Tregs, concurrent with the increase in commensal-specific Th17 cells. These results align with recent human data suggesting that commensal-specific T cells switch from tolerogenic cells in healthy individuals to inflammatory IL-17–secreting cells in patients with active Crohn’s disease ( 14 , 67 ). While the composition of commensal bacteria differs in HDAC3 ΔIEC versus MHCII ΔIEC mouse models, both models exhibited a similar increase in cBir1 + commensal-specific CD4 + T cells.…”

Section: Discussionsupporting

confidence: 91%

“…In addition, elevated commensal-specific Th17 cells were also found in mice with loss of epithelial MHCII. Remarkably, patients with active IBD have functionally distinct microbiota-reactive CD4 + T cells, compared to those found in healthy controls, and secrete higher levels of IL-17 (14,26,(28)(29)(30)67). IL-17 has been linked to development and exacerbation of several autoimmune and inflammatory conditions, including IBD (28,30,87).…”

Section: Studies On Epithelial Mhcii In Controlling Intestinalmentioning

confidence: 99%

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Intestinal epithelial HDAC3 and MHC class II coordinate microbiota-specific immunity

Eshleman¹,

Shao²,

Woo³

et al. 2023

Journal of Clinical Investigation

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Aberrant immune responses to resident microbes promote inflammatory bowel disease and other chronic inflammatory conditions. However, how microbiota-specific immunity is controlled in mucosal tissues remains poorly understood. Here, we find that mice lacking epithelial expression of microbiota-sensitive histone deacetylase 3 (HDAC3) exhibit increased accumulation of commensal-specific CD4 + T cells in the intestine, provoking the hypothesis that epithelial HDAC3 may instruct local microbiota-specific immunity.Consistent with this, microbiota-specific CD4 + T cells and epithelial HDAC3 expression were concurrently induced following early-life microbiota colonization. Further, epithelialintrinsic ablation of HDAC3 decreased commensal-specific Tregs, increased commensalspecific Th17 cells, and promoted T cell-driven colitis. Mechanistically, HDAC3 was essential for NFκB-dependent regulation of epithelial MHC class II (MHCII). Epithelialintrinsic MHCII dampened local accumulation of commensal-specific Th17 cells in adult mice, and protected against microbiota-triggered inflammation. Remarkably, HDAC3 enabled the microbiota to induce MHCII on epithelial cells and limit the number of commensal-specific T cells in the intestine. Collectively, these data reveal a central role for an epithelial histone deacetylase in directing the dynamic balance of tissue-intrinsic CD4 + T cell subsets that recognize commensal microbes and control inflammation.

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Section: Discussionsupporting

confidence: 91%

Section: Studies On Epithelial Mhcii In Controlling Intestinalmentioning

confidence: 99%

Intestinal epithelial HDAC3 and MHC class II coordinate microbiota-specific immunity

Eshleman¹,

Shao²,

Woo³

et al. 2023

Journal of Clinical Investigation

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“…The most prevalent genomic regions that demonstrated differential orientations of invertible regions were in susC/susD homologs and polysaccharide (PS) promoters -both with immunomodulatory potential. An epitope of SusC-like proteins, part of the starch-utilization system in Bacteroidetes, was recently shown to elicit T cell responses in IBD patients and healthy controls 45 , suggesting that operons that include SusC homologs might confer immunomodulatory properties to the bacteria, and phase variation in such genes might alter bacteria-host interactions. Among the phase-variable PSs, the anti-inflammatory polysaccharide A (PSA) promoter of B. fragilis showed a higher percentage of reverse oriented reads in IBD patients compared to healthy controls, indicating that the 'OFF' orientation was more prevalent in IBD patients, potentially limiting the protective, anti-inflammatory, effects of PSA.…”

Section: Discussionmentioning

confidence: 99%

Inflammation and bacteriophages affect DNA inversion states and functionality of the gut microbiota

Carasso

Zaatry

Hajjo

et al. 2023

Preprint

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Reversible genomic DNA-inversions control expression of numerous bacterial molecules in the human gut, but how this relates to disease remains uncertain. By analyzing metagenomic samples from six human Inflammatory Bowel Disease (IBD) cohorts combined with mice experimentation, we identified multiple invertible regions in which a particular orientation was correlated with disease. These include the promoter of the anti-inflammatory polysaccharide-A (PSA) ofBacteroides fragilis, which is mostly oriented OFF during inflammation but switches to the ON orientation when inflammation is resolved. We further detected increased abundances ofBacteroides fragilisassociated bacteriophages in patients with the PSA OFF orientation. Isolation and analysis of aBacteroides fragilisassociated bacteriophage revealed that it induced the PSA OFF switch, thereby altering the bacterial induced immune modulation. Altogether, we reveal large-scale dynamic and reversible bacterial phase variations driven both by bacteriophages and the host inflammatory state signifying bacterial functional plasticity and suggesting potential clinical interventions.

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“…165 Emerging T cell-antigen discovery approaches within the microbiome may provide an exciting field for upcoming studies. 166 In case of autoantigen-mediated pathology, it may be possible to specifically negate T cell interaction by antibodies or small compounds that specifically block access to MHC-Ipeptide complexes. T-cell engagement may also be blocked by preventing or changing the abundance of target peptide presentation by manipulation upstream of MHC-I, including the cellular proteome (eg, chemotherapy), or pharmacological inhibition or modulation of the proteasome, TAP or the antigen loading complex, [167][168][169][170][171] although with limitations in specificity at the cost of potential adverse effects.…”

Section: Towards Mhc-i Pathway Therapymentioning

confidence: 99%

EULAR study group on ‘MHC-I-opathy’: identifying disease-overarching mechanisms across disciplines and borders

et al. 2023

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The ‘MHC-I (major histocompatibility complex class I)-opathy’ concept describes a family of inflammatory conditions with overlapping clinical manifestations and a strong genetic link to the MHC-I antigen presentation pathway. Classical MHC-I-opathies such as spondyloarthritis, Behçet’s disease, psoriasis and birdshot uveitis are widely recognised for their strong association with certain MHC-I alleles and gene variants of the antigen processing aminopeptidases ERAP1 and ERAP2 that implicates altered MHC-I peptide presentation to CD8+T cells in the pathogenesis. Progress in understanding the cause and treatment of these disorders is hampered by patient phenotypic heterogeneity and lack of systematic investigation of the MHC-I pathway.Here, we discuss new insights into the biology of MHC-I-opathies that strongly advocate for disease-overarching and integrated molecular and clinical investigation to decipher underlying disease mechanisms. Because this requires transformative multidisciplinary collaboration, we introduce the EULAR study group on MHC-I-opathies to unite clinical expertise in rheumatology, dermatology and ophthalmology, with fundamental and translational researchers from multiple disciplines such as immunology, genomics and proteomics, alongside patient partners. We prioritise standardisation of disease phenotypes and scientific nomenclature and propose interdisciplinary genetic and translational studies to exploit emerging therapeutic strategies to understand MHC-I-mediated disease mechanisms. These collaborative efforts are required to address outstanding questions in the etiopathogenesis of MHC-I-opathies towards improving patient treatment and prognostication.

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The CD4+ T cell response to a commensal-derived epitope transitions from a tolerant to an inflammatory state in Crohn’s disease

Cited by 25 publications

References 90 publications

Intestinal epithelial HDAC3 and MHC class II coordinate microbiota-specific immunity

Intestinal epithelial HDAC3 and MHC class II coordinate microbiota-specific immunity

Inflammation and bacteriophages affect DNA inversion states and functionality of the gut microbiota

EULAR study group on ‘MHC-I-opathy’: identifying disease-overarching mechanisms across disciplines and borders

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