Human Intestinal Dendritic Cells Can Overcome Retinoic Acid Signaling to Generate Proinflammatory CD4 T Cells with Both Gut and Skin Homing Properties

Abstract

Abstract Retinoic acid, produced by intestinal dendritic cells (DCs), promotes T cell trafficking to the intestinal mucosa by upregulating α4β7 integrin and inhibiting the generation of cutaneous leukocyte Ag (CLA) required for skin entry. In the present study, we report that activation of human naive CD4 T cells in an APC-free system generates cells expressing α4β7 alone; in contrast, activation by intestinal DCs that produce retinoic acid and induce high levels of α4β7 also results in CLA expression, generating CLA+α4β7+ “dual tropic” cells, with both gut and skin trafficking potential, that also express high levels of α4β1 integrin. DC generation of CLA+α4β7+ T cells is associated with upregulation of FUT7, a fucosyltransferase involved in CLA generation; requires cell contact; and is enhanced by IL-12/IL-23. The blood CD4+ T cell population contains CLA+α4β7+ cells, which are significantly enriched for cells capable of IFN-γ, IL-17, and TNF-α production compared with conventional CLA−α4β7+ cells. Dual tropic lymphocytes are increased in intestinal tissue from patients with Crohn’s disease, and single-cell RNA-sequencing analysis identifies a transcriptionally distinct cluster of FUT7-expressing cells present only in inflamed tissue; expression of genes associated with cell proliferation suggests that these cells are undergoing local activation. The expression of multiple trafficking molecules by CLA+α4β7+ T cells can enable their recruitment by alternative pathways to both skin and gut; they may contribute to both intestinal and cutaneous manifestations of inflammatory bowel disease.