Induction of tolerogenic T cells in the gut by probiotics probiotics t cells

When CD4+ T cells reach the small intestinal epithelium, they can reactivate the CD8 T cell lineage program and differentiate into CD4+CD8+ T cells (also known as double-positive intraepithelial lymphocytes (DP IELs)), which promote tolerance to dietary antigens, in part by downregulating levels of the transcription factor THPOK. Cervantes-Barragan et al. now show that Lactobacillus reuteri, a kind of probiotic bacterium, causes CD4+ T cells to differentiate into DP IELs by activating their aryl hydrocarbon receptor (AHR), resulting in a drop in THPOK levels. probioticseverything.comprobiotics t cellsprobiotics t cells

The researchers discovered that DP IELs were present in Charles River Laboratories (CR) mice but not in Jackson Laboratories (JAX) mice, and that the DP IEL-positive phenotype could be transferred to JAX mice by colonization them with CR mice’s ileal or faecal microbiota. Treatment of CR mice with antibiotics that target Gram-positive bacteria prevented the development of DP IELs, implying that Gram-positive bacteria in the stomach cause DP IELs. L. reuteri was found in the ilea of CR but not JAX mice, and two L. reuteri strains caused DP IELs in JAX mice. probioticseverything.comprobiotics t cellsprobiotics t cells

The scientists discovered that L. reuteri metabolizes dietary tryptophan to indole compounds that activate AHR, and that cell-free supernatant from L. reuteri cultured in tryptophan-containing media, as well as an AHR agonist, encouraged the differentiation of CD4+ T cells into DP IELs. An AHR antagonist, on the other hand, stopped CD4+ T cells from becoming DP IELs. These findings indicate that the L. reuteri supernatant acts via AHR. Indeed, an L. reuteri mutant that is unable to convert tryptophan into AHR ligands was unable to induce DP IELs in JAX mice, and the frequency of DP IELs was lower in mice with Ahr/ T cells compared to wild-type littermates. Further evidence suggests that AHR deficiency prevents IEL differentiation into DP IELs upstream of THPOK downregulation. probioticseverything.comprobiotics t cellsprobiotics t cells

In conclusion, L. reuteri causes DP IELs via activating AHR, which causes THPOK to be downregulated. A high-tryptophan diet increased the frequency of DP IELs in CR mice, but it failed to generate DP IELs in germ-free mice monocolonized with L. reuteri, implying that L. reuteri operates as part of the microbiota to induce DP IELs in the presence of tryptophan. probioticseverything.comprobiotics t cellsprobiotics t cells

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