23 TLR/MYD88-Dependent Production of Il1β and IL-23 by Intestinal Dendritic Cells Support Increased Ilc Production of IL-22 in IBD

Abstract

cells, imprinting gut homing expression on responding lymphocytes, and facilitating IgA production. How CD103+ LP-DCs become imprinted to produce ATRA is not well understood. In vitro studies have shown that epithelial cells can condition DCs to express retinaldehye dehydrogenase (ALDH1), the enzyme required for the final irreversible step in ATRA production, and in vivo studies have shown that luminal retinoids from the diet or bile, as opposed to systemic retinoids, are required to condition intestinal LP-DCs with the capacity to generate ATRA. Through the formation of goblet cell associated antigen passages (GAPs), the small intestine epithelium provides a portal for CD103+ LP-DCs to acquire soluble substances from the intestinal lumen. Moreover during the transfer of luminal substances, CD103+ LP-DCs physically interact with goblet cells (GCs) and acquire GC proteins. These observations suggest a role for GCs and GAPs in imprinting CD103+ LP-DCs. Using an in vivo two-photon (2P) imaging approach, we evaluated if and how LP-DCs acquire luminal retinoids. We observed that GAPs delivered luminal beta-carotene and the enzyme required to metabolize beta-carotene to LP-DCs. Moreover in the absence of GCs, LP-DCs are not imprinted with ALDH activity. We observed that LP-DCs express CCR6, which was required for LP-DCs to associate with the small intestine epithelium. As a consequence of impaired association with the epithelium, CCR6 deficient LP-DCs do not acquire GC proteins or luminal antigens, do not become conditioned with ALDH activity, and are impaired at inducing ATRA dependent events in responding lymphocytes. These findings demonstrate that GAPs deliver luminal retinoids and the enzymes required to metabolize these retinoids to CD103+ LP-DCs, and accordingly GCs play a critical role in imprinting CD103+ LPDCs. Thus GAPs deliver luminal antigens, immunomodulatory dietary substances, and epithelial proteins simultaneously to CD103+ LP-DCs to shape intestinal immune responses to small soluble luminal antigens.