Inflammation

Human intestinal epithelial cells promote the differentiation of tolerogenic dendritic cells

I D Iliev¹, I Spadoni¹, E Mileti¹, G Matteoli¹, A Sonzogni², G M Sampietro³, D Foschi³, F Caprioli⁴, G Viale², M Rescigno¹

¹ Department of Experimental Oncology, European Institute of Oncology, Milan, Italy
² Department of Pathology and Laboratory Medicine, European Institute of Oncology, Milan, Italy
³ Department of Surgery, II Division of General Surgery, Universita degli Studi di Milano, Ospedale Luigi Sacco, Milan, Italy
⁴ Unità Operativa di Gastroenterologia 2, IRCCS Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena, Milan, Italy

^{Correspondence to} Dr M Rescigno, Department of Experimental Oncology, European Institute of Oncology, Via Ripamonti 435, 20141 Milan, Italy; maria.rescigno{at}ifom-ieo-campus.it

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 β (TGFβ), 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.

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