Chemokine (C-C motif) receptor 2 mediates dendritic cell recruitment to the human colon but is not responsible for differences observed in dendritic cell subsets, phenotype, and function between the proximal and distal colon

Open Access funded by Biotechnology and Biological Sciences Research Council. Under a Creative Commons license.-- et al.[Background & Aims]: Most knowledge about gastrointestinal (GI)-tract dendritic cells (DC) relies on murine studies where CD103 DC specialize in generating immune tolerance with the functionality of CD11b subsets being unclear. Information about human GI-DC is scarce, especially regarding regional specifications. Here, we characterized human DC properties throughout the human colon. [Methods]: Paired proximal (right/ascending) and distal (left/descending) human colonic biopsies from 95 healthy subjects were taken; DC were assessed by flow cytometry and microbiota composition assessed by 16S rRNA gene sequencing. [Results]: Colonic DC identified were myeloid (mDC, CD11cCD123) and further divided based on CD103 and SIRPα (human analog of murine CD11b) expression. CD103SIRPα DC were the major population and with CD103SIRPα DC were CD1cILT3CCR2 (although CCR2 was not expressed on all CD103SIRPα DC). CD103SIRPα DC constituted a minor subset that were CD141ILT3CCR2. Proximal colon samples had higher total DC counts and fewer CD103SIRPα cells. Proximal colon DC were more mature than distal DC with higher stimulatory capacity for CD4CD45RA T-cells. However, DC and DC-invoked T-cell expression of mucosal homing markers (β7, CCR9) was lower for proximal DC. CCR2 was expressed on circulating CD1c, but not CD141 mDC, and mediated DC recruitment by colonic culture supernatants in transwell assays. Proximal colon DC produced higher levels of cytokines. Mucosal microbiota profiling showed a lower microbiota load in the proximal colon, but with no differences in microbiota composition between compartments. [Conclusions]: Proximal colonic DC subsets differ from those in distal colon and are more mature. Targeted immunotherapy using DC in T-cell mediated GI tract inflammation may therefore need to reflect this immune compartmentalization.This study was funded by the Biotechnology and Biological Sciences Research Council, BBSRC Institute Strategic Programme for Gut Health and Food Safety, grant BB/J004529/1; 16S rRNA gene sequencing was provided by the Wellcome Trust (grant number WT 098051) (to P.S., J.P., A.W.W.); core funding support from the Scottish Government Rural and Environmental Science and Analysis Service (to A.W.W. and the Rowett Institute of Nutrition and Health, University of Aberdeen); the Association for International Cancer Research (AICR), Scotland, grant number 120234 (to H.O.A.); and the Junta de Castilla y León, Spain (SAN196/VA16/07 and SAN196/VA17/07).Peer Reviewe