CCR2 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
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Published version
Accepted version
Author(s)
Type
Journal Article
Abstract
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, CD11c+CD123-) and further divided based on CD103 and SIRPα (human analog of murine CD11b) expression. CD103-SIRPα+ DC were the major population and with CD103+SIRPα+ DC were CD1c+ILT3+CCR2+ (although CCR2 was not expressed on all CD103+SIRPα+ DC). CD103+SIRPα- DC constituted a minor subset that were CD141+ILT3-CCR2-. Proximal colon samples had higher total DC counts and fewer CD103+SIRPα+ 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 (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 being more mature. Targeted immunotherapy using DC in T-cell mediated GI-tract inflammation may therefore need to reflect this immune compartmentalization.
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, CD11c+CD123-) and further divided based on CD103 and SIRPα (human analog of murine CD11b) expression. CD103-SIRPα+ DC were the major population and with CD103+SIRPα+ DC were CD1c+ILT3+CCR2+ (although CCR2 was not expressed on all CD103+SIRPα+ DC). CD103+SIRPα- DC constituted a minor subset that were CD141+ILT3-CCR2-. Proximal colon samples had higher total DC counts and fewer CD103+SIRPα+ 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 (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 being more mature. Targeted immunotherapy using DC in T-cell mediated GI-tract inflammation may therefore need to reflect this immune compartmentalization.
Date Issued
2015-09-02
Date Acceptance
2015-08-21
Citation
Cellular and Molecular Gastroenterology and Hepatology, 2015, 2 (1), pp.22-39.e5
ISSN
2352-345X
Publisher
Elsevier
Start Page
22
End Page
39.e5
Journal / Book Title
Cellular and Molecular Gastroenterology and Hepatology
Volume
2
Issue
1
Copyright Statement
© 2015 The Authors. Under a Creative Commons Attribution (CC BY 4.0)
License URL
Sponsor
Biotechnology and Biological Sciences Research Cou
Grant Number
PR5858-000-A
Subjects
human gastrointestinal tract
dendritic cells
proximal colon
distal colon
microbiota
CCR2
Publication Status
Published