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 utilize 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). Adoptively transferred transgenic T cells expressing the BθOM TCR proliferated in the colon, colon-draining lymph node, and spleen in B. theta colonized healthy mice and differentiated into regulatory T (Treg) and effector T (Teff) cells. 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 BθOM 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 BθOM 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.

Intestinal IgA Regulates Expression of a Fructan Polysaccharide Utilization Locus in Colonizing Gut Commensal Bacteroides thetaiotaomicron

“…In line with this idea, a recent finding reported a diet-dependent antigen from B. thetaiotaomicron (BT4295) to be a specific target of host CD4 + T cell response in the murine gut (17). To our knowledge, these dietary MAC utilization loci have not been implicated in bacterial virulence and thus could represent true commensal targets of gut IgA surveillance.…”

“…B. thetaiotaomicron, a prominent human gut bacterium with a fully sequenced genome, induces a homeostatic, noninflammatory intestinal IgA response upon colonization of germfree mice and serves as a good candidate to study the gut immune response to colonizing commensals (13–15, 17). To identify B.…”

Understanding immune–microbiota interactions in the intestine

“…A variety of bacterial strains from distinct phyla, operating individually or as part of multi-strain consortia, prime the accumulation of peripherally derived colonic Treg cells and the production of the immune suppressive cytokine IL-10. These include Clostridia from clusters IV, XIVa and XVIII (Firmicutes), 48,54 various Bacteroides species (Bacteroidetes) 68,78,83,96 or Helicobacter species (Proteobacteria), [97][98][99] Bifidobacterium bifidum (Actinobacteria), 100 and the Altered Schaedler Flora (multiple phyla). 101 An isolate of Bifidobacterium adolescentis (an Actinobacteria) obtained from humans that could induce Th17 cells was also identified, confirming that this was not unique to SFB.…”

Glycan Utilisation and Function in the Microbiome of Weaning Infants

“…B. thetaiotamicron generates numerous bacterial antigens with outer membrane vesicles that express sulfatases allowing them to access host immune cell, which promote inflammatory immune stimulation [120]. Recently, dietary factors have been found to regulate the expression outer membrane vesicle antigens: a high glucose diet reduced protein expression of a peptide that is both recognised by T cells and stimulates the differentiation into T reg cells and effector T cells, with depletion of T reg cells resulting in colitis [122]. The increased availability of glucose in the lumen from extracellular degradation of complex glycans may generate steady concentrations of glucose that regulate differentiation pathways of immune factors.…”