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Human intestinal epithelial cells promote the differentiation of tolerogenic dendritic cells.
  1. Iliyan D Iliev (iliyandimitrov.iliev{at}ifom-ieo-campus.it)
  1. European Institute of Oncology, Italy
    1. Ilaria Spadoni
    1. European Institute of Oncology, Italy
      1. Erika Mileti
      1. European Institute of Oncology, Italy
        1. Gianluca Matteoli
        1. European Institute of Oncology, Italy
          1. Angelica Sonzogni
          1. European Institute of Oncology, Italy
            1. Gianluca M Sampietro
            1. Ospedale Luigi Sacco, Italy
              1. Diego Foschi
              1. /, Italy
                1. Flavio Caprioli
                1. Mangiagalli e Regina Elena, Milan, Italy
                  1. Giuseppe Viale
                  1. European Institute of Oncology, Italy
                    1. Maria Rescigno (maria.rescigno{at}ifom-ieo-campus.it)
                    1. European Institute of Oncology, Italy

                      Abstract

                      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.

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