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 Prpximal and Distal Colon

BACKGROUND & AIMS: Most knowledge about gastrointestinal (GO-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, CD11c(+)CD123(-) ) and further divided based on CD103 and SIRP alpha (human analog of murine CD11b) expression. CD103 SIRP alpha(+) DC were the major population and with CD103(+) SIRP alpha(+) DC were CD1c(+) ILT3(+)CCR2(+) (although CCR2 was not expressed on all CD103(+) SIRP alpha(+) DC). CD103(+)SIRP alpha(-) DC constituted a minor subset that were CD141(+)ILT3(-)CCR2(-). Proximal colon samples had higher total DC counts and fewer CD103(+)SIRP alpha(+) cells. Proximal colon DC were more mature than distal DC with higher stimulatory capacity for CD4(+)CD45RA(+) T-cells. However, DC and DC-invoked T-cell expression of mucosal homing markers (beta 7, 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.