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Human intestinal epithelial cells promote the differentiation of tolerogenic dendritic cells
  1. I D Iliev1,
  2. I Spadoni1,
  3. E Mileti1,
  4. G Matteoli1,
  5. A Sonzogni2,
  6. G M Sampietro3,
  7. D Foschi3,
  8. F Caprioli4,
  9. G Viale2,
  10. M Rescigno1
  1. 1
    Department of Experimental Oncology, European Institute of Oncology, Milan, Italy
  2. 2
    Department of Pathology and Laboratory Medicine, European Institute of Oncology, Milan, Italy
  3. 3
    Department of Surgery, II Division of General Surgery, Universita degli Studi di Milano, Ospedale Luigi Sacco, Milan, Italy
  4. 4
    Unità Operativa di Gastroenterologia 2, IRCCS Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena, Milan, Italy
  1. 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

Abstract

Objective: In mice, a subpopulation of gut dendritic cells (DCs) expressing CD103 drives the development of regulatory T (Treg) 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 Treg 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 Treg cell differentiation experiments.

Results: It was found that human IECs promoted the differentiation of tolerogenic DCs able to drive the development of adaptive Foxp3+ Treg 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 Treg 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 Treg cell development.

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Footnotes

  • Funding This study was supported by the Crohn’s and Colitis Foundation of America (CCFA to MR); Italian Association for Cancer Research (AIRC to MR); European Research Council (ERC to MR); and the EC 7th Framework Program (IBDase, METAhit to MR).

  • Competing interests None.

  • Provenance and Peer review Not commissioned; externally peer reviewed.

  • Ethics approval The local ethics committee approved the informed consent specifying that material not needed for diagnostic purposes could be used for research purposes.

  • ▸ A more detailed description of the methods and additional figures are published online only at http://gut.bmj.com/content/vol58/issue11

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