Human intestinal epithelial cells promote the differentiation of tolerogenic dendritic cells

Objective: In mice, a subpopulation of gut dendritic cells (DCs) expressing CD103 drives the development of regulatory T (T-reg) cells. Further, it was recently described that the cross-talk between human intestinal epithelial cells (IECs) and DCs helps in maintaining gut immune homeostasis via the induction of non-inflammatory DCs. In this study, an analysis was carried out to determine whether IECs could promote the differentiation of CD103(+) tolerogenic DCs, and the function of primary CD103(+) DCs isolated from human mesenteric lymph nodes (MLNs) was evaluated. Methods: Monocyte-derived DCs (MoDCs) and circulating CD1c(+) DCs were conditioned or not with supernatants from Caco-2 cells or IECs isolated from healthy donors or donors with Crohn's disease and analysed for their ability to induce T-reg cell differentiation. In some cases, transforming growth factor beta (TGF beta), retinoic acid (RA) or thymic stromal lymphopoietin (TSLP) were neutralised before conditioning. CD103(+) and CD103(-) DCs were sorted by fluorescence-activated cell sorting (FACS) from MLNs and used in T-reg cell differentiation experiments. Results: It was found that human IECs promoted the differentiation of tolerogenic DCs able to drive the development of adaptive Foxp3(+) T-reg cells. This control was lost in patients with Crohn's disease and paralleled a reduced expression of tolerogenic factors by primary IECs. MoDCs differentiated with RA or IEC supernatant upregulated the expression of CD103. Consistently, human primary CD103(+) DCs isolated from MLNs were endowed with the ability to drive T-reg cell differentiation. This subset of DCs expressed CCR7 and probably represents a lamina propria-derived migratory population. Conclusions: A population of tolerogenic CD103(+) DCs was identified in the human gut that probably differentiate in response to IEC-derived factors and drive T-reg cell development.