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 <i>Clostridium Faecalibacterium prausnitzii (F. prausnitzii)</i>, 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 <i>Clostridium</i> bacteria are key players in colon homeostasis, support a similar role for <i>F. prausnitzii</i>-specific Treg in the human colon. Here we assessed the mechanisms whereby <i>F. prausnitzii</i> induces human colonic Treg. We demonstrated that <i>F. prausnitzii</i>, but not related Clostridia, skewed human dendritic cells to prime IL-10-secreting T cells. Accordingly, <i>F. prausnitzii</i> 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 <i>F. prausnitzii</i>-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 <i>F. prausnitzii</i>-specific Tr1-like Treg in the human colon, point out to dendritic cells polarization by <i>F. prausnitzii</i> as the first described cellular mechanism whereby the microbiota composition may affect human colon homeostasis. Identification of <i>F. prausnitzii</i>-induced mediators involved in Tr1-like Treg induction by dendritic cells opens therapeutic avenues for the treatment of inflammatory bowel diseases.