Faecalibacterium prausnitzii Skews Human DC to Prime IL10-Producing T Cells Through TLR2/6/JNK Signaling and IL-10, IL-27, CD39, and IDO-1 Induction

Abstract

The human colonic mucosa contains regulatory type 1-like (Tr1-like, i.e., IL-10-secreting and Foxp3-negative) T cells specific for the gut Clostridium Faecalibacterium prausnitzii (F. prausnitzii), which are both decreased in Crohn's disease patients. These data, together with the demonstration, in mice, that colonic regulatory T cells (Treg) induced by Clostridium bacteria are key players in colon homeostasis, support a similar role for F. prausnitzii-specific Treg in the human colon. Here we assessed the mechanisms whereby F. prausnitzii induces human colonic Treg. We demonstrated that F. prausnitzii, but not related Clostridia, skewed human dendritic cells to prime IL-10-secreting T cells. Accordingly, F. prausnitzii induced dendritic cells to express a unique array of potent Tr1/Treg polarizing molecules: IL-10, IL-27, CD39, IDO-1, and PDL-1 and, following TLR4 stimulation, inhibited their up-regulation of costimulation molecules as well as their production of pro-inflammatory cytokines IL-12 (p35 and p40) and TNFα. We further showed that these potent tolerogenic effects relied on F. prausnitzii-induced TLR2/6 triggering, JNK signaling and CD39 ectonucleotidase activity, which was induced by IDO-1 and IL-27. These data, together with the presence of F. prausnitzii-specific Tr1-like Treg in the human colon, point out to dendritic cells polarization by F. prausnitzii as the first described cellular mechanism whereby the microbiota composition may affect human colon homeostasis. Identification of F. prausnitzii-induced mediators involved in Tr1-like Treg induction by dendritic cells opens therapeutic avenues for the treatment of inflammatory bowel diseases.

Microbiota Modulating Nutritional Approaches to Countering the Effects of Viral Respiratory Infections Including SARS-CoV-2 through Promoting Metabolic and Immune Fitness with Probiotics and Plant Bioactives

“…B. longum strains have been demonstrated to cause changes in the level of specific Bifidobacterium species in the elderly that correlated with TNF-α, TGF-β, and IL-10 levels in serum [117]. The daily consumption of Bacillus coagulans BC30 PB spores has been shown to significantly increase the populations of Faecalibacterium prausnitzii, with concomitant increases in anti-inflammatory IL-10 levels in elderly subjects [118], supporting the direct correlation confirmed by another study [119]. B. coagulans BC30 has been confirmed in ex vivo experiments to increase the T-cell production of TNF-α in response to specific adenovirus and influenza virus exposures [71].…”

IDO and Kynurenine Metabolites in Peripheral and CNS Disorders

“…The relationship between IDO and IL-10 may be particularly relevant in the presence of microbial invasion since some bacteria can induce DCs to facilitate IL-10 production by subpopulations of T cells such as the FoxP3-negative Tr1-like cells. This is achieved by the microbial induction of appropriate T cell polarizing molecules including IDO1 (189). Consistent with the overall anti-inflammatory balance which this generates, the production of IDO1 and IL-10 is accompanied by a reduction in the secretion of pro-inflammatory TNF-α and IL-12 components.…”

Mycobacterium lepraeinduces a tolerogenic profile in monocyte-derived dendritic cells via TLR2 induction of IDO

“…27 In addition, it was demonstrated that tolerogenic effects induced by IDO-1 depend on TLR2/6-induced JNK signaling by Faecalibacterium prausnitzii and ectonucleotidase activity. 28 A key mechanism involved in mDCs-mediated immunosuppression is the expression of IDO-1. 31 The interaction of DCs with TLR2 and TLR4 treated with ES L1 (excretory-secretory muscle larvae) promotes the expansion of CD4 + CD25 high Foxp3 high producing IL-10 and TGF-cells in an IDO-1-dependent form.…”