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Diet modulates colonic T cell responses by regulating the expression of a Bacteroides thetaiotaomicron antigen.

ABSTRACT: T cell responses to symbionts in the intestine drive tolerance or inflammation depending on the genetic background of the host. These symbionts in the gut sense the available nutrients and adapt their metabolic programs to use these nutrients efficiently. Here, we ask whether diet can alter the expression of a bacterial antigen to modulate adaptive immune responses. We generated a CD4+ T cell hybridoma, B?OM, specific for Bacteroides thetaiotaomicron (B. theta). Adoptively transferred transgenic T cells expressing the B?OM TCR proliferated in the colon, colon-draining lymph node, and spleen in B. theta-colonized healthy mice and differentiated into regulatory T cells (Tregs) and effector T cells (Teffs). Depletion of B. theta-specific Tregs resulted in colitis, showing that a single protein expressed by B. theta can drive differentiation of Tregs that self-regulate Teffs to prevent disease. We found that B?OM T cells recognized a peptide derived from a single B. theta protein, BT4295, whose expression is regulated by nutrients, with glucose being a strong catabolite repressor. Mice fed a high-glucose diet had a greatly reduced activation of B?OM T cells in the colon. These studies establish that the immune response to specific bacterial antigens can be modified by changes in the diet by altering antigen expression in the microbe.

SUBMITTER: Wegorzewska MM

PROVIDER: S-EPMC6550999 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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Diet modulates colonic T cell responses by regulating the expression of a Bacteroides thetaiotaomicron antigen.

Wegorzewska Marta M MM Glowacki Robert W P RWP Hsieh Samantha A SA Donermeyer David L DL Hickey Christina A CA Horvath Stephen C SC Martens Eric C EC Stappenbeck Thaddeus S TS Allen Paul M PM

Science immunology 20190201 32

T cell responses to symbionts in the intestine drive tolerance or inflammation depending on the genetic background of the host. These symbionts in the gut sense the available nutrients and adapt their metabolic programs to use these nutrients efficiently. Here, we ask whether diet can alter the expression of a bacterial antigen to modulate adaptive immune responses. We generated a CD4+ T cell hybridoma, BθOM, specific for Bacteroides thetaiotaomicron (B. theta). Adoptive ...[more]

PMID: 30737355

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Project description:BackgroundInflammatory bowel diseases (IBD) may be caused in part by aberrant immune responses to commensal intestinal microbes including the well-characterized anaerobic gut commensal Bacteroides thetaiotaomicron (B. theta). Healthy, germ-free HLA-B27 transgenic (Tg) rats develop chronic colitis when colonized with complex gut commensal bacteria whereas non-transgenic (nTg) rats remain disease-free. However, the role of B. theta in causing disease in Tg rats is unknown nor is much known about how gut microbes respond to host inflammation.MethodsTg and nTg rats were monoassociated with a human isolate of B. theta. Colonic inflammation was assessed by histologic scoring and tissue pro-inflammatory cytokine measurement. Whole genome transcriptional profiling of B. theta recovered from ceca was performed using custom GeneChips and data analyzed using dChip, Significance Analysis of Microarrays, and Gene Set Enrichment Analysis (GSEA) software. Western Blots were used to determine adaptive immune responses to a differentially expressed B. theta gene.ResultsB. theta monoassociated Tg rats, but not nTg or germ-free controls, developed chronic colitis. Transcriptional profiles of cecal B. theta were significantly different in Tg vs. nTg rats. GSEA revealed that genes in KEGG canonical pathways involved in bacterial growth and metabolism were downregulated in B. theta from Tg rats with colitis though luminal bacterial concentrations were unaffected. Bacterial genes in the Gene Ontology molecular function "receptor activity", most of which encode nutrient binding proteins, were significantly upregulated in B. theta from Tg rats and include a SusC homolog that induces adaptive immune responses in Tg rats.ConclusionsB. theta induces colitis in HLA-B27 Tg rats, which is associated with regulation of bacterial genes in metabolic and nutrient binding pathways that may affect host immune responses. These studies of the host-microbial dialogue may lead to the identification of novel microbial targets for IBD therapies.

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Diet modulates colonic T cell responses by regulating the expression of a Bacteroides thetaiotaomicron antigen.

Publications

Diet modulates colonic T cell responses by regulating the expression of a <i>Bacteroides thetaiotaomicron</i> antigen.

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