Objective: In mice, a subpopulation of gut dendritic cells (DCs) expressing CD103 drives the development of regulatory T cells (Treg). Further, we recently described that the cross-talk between human intestinal epithelial cells (IEC) and DCs helps maintaining gut immune homeostasis via the induction of non-inflammatory DCs. In this study, we analyzed whether human IEC could promote the differentiation of CD103+ tolerogenic DCs and evaluated the function of primary CD103+ DCs isolated from mesenteric lymph nodes (MLNs).
Methods: Monocyte (Mo)-derived-DCs and circulating CD1c+ DCs were conditioned or not with supernatants from Caco-2 cells or IEC isolated from healthy or Crohn’s disease donors and analyzed for their ability to induce Treg cell differentiation. In some cases TGF-β, Retinoic acid (RA) or Thymic-stromal lymphopoietin (TSLP) were neutralized before conditioning. CD103+ and CD103- DCs were FACS-sorted from MLNs and used in Treg cell differentiation experiments.
Results: We found that human IEC promoted the differentiation of tolerogenic DCs able to drive the development of adaptive Foxp3+ Treg cells. This control was lost in Crohn patients and paralleled a reduced expression of tolerogenic factors by primary IECs. MoDCs differentiated with RA or EC supernatant upregulated the expression of CD103. Consistently, human primary CD103+ DCs isolated from MLNs were endowed with the ability to drive Treg differentiation. This subset of DCs expressed CCR7 and likely represents a lamina propria-derived migratory population.
Conclusions: We identified a population of tolerogenic CD103+ DCs in the human gut that likely differentiate in response to IEC-derived factors and drive Treg development.