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Strain specific maturation of Dendritic cells and production of IL-1β controls CD40-driven colitis.
PLoS ONE 14:e0210998 (2019)
Intestinal integrity is maintained by balanced numbers of CD103(+) Dendritic cells (DCs), which generate peripherally induced regulatory T cells (iTregs). We have developed a mouse model where DC-specific constitutive CD40 signals caused a strong reduction of CD103(+) DCs in the lamina propria (LP) and intestinal lymph nodes (LN). As a consequence, also iTregs were strongly reduced and transgenic mice on the C57Bl/6-background (B6) developed fatal colitis. Here we describe that transgenic mice on a pure Balb/c-background (B/c) do not show any pathologies, while transgenic C57Bl/6 x Balb/c (F1) mice develop weak colon inflammation, without fatal colitis. This graded pathology correlated with the effects of CD40-signalling on DCs in each background, with striking loss of CD103(+) DCs in B6, but reduced in F1 and diminished in B/c background. We further show direct correlation of CD103(+) DC-numbers with numbers of iTregs, the frequencies of which behave correspondingly. Striking effects on B6-DCs reflected robust loss of surface MHCII, known to be crucial for iTreg induction. Furthermore, elevated levels of IL-23 together with IL-1, found only in B6 mice, support generation of intestinal IFN-gamma(+) IL-17(+) Th17 cells and IFN-gamma(+) Th1 cells, responsible for onset of disease. Together, this demonstrates a novel aspect of colitis-control, depending on genetic background. Moreover, strain-specific environmental sensing might alter the CD103(+) DC/iTreg-axis to tip intestinal homeostatic balance to pathology.
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Publication type
Article: Journal article
Document type
Scientific Article
Keywords
Regulatory T-cells; Inflammatory-bowel-disease; Soluble Cd40 Ligand; Transcription-factor; Tgf-beta; Intestinal Inflammation; Signaling Controls; Cd103(+) Dcs; Th1 Cells; Reg-cells
ISSN (print) / ISBN
1932-6203
Journal
PLoS ONE
Quellenangaben
Volume: 14,
Issue: 1,
Article Number: e0210998
Publisher
Public Library of Science (PLoS)
Publishing Place
Lawrence, Kan.
Non-patent literature
Publications
Reviewing status
Peer reviewed
Institute(s)
Research Unit Analytical Pathology (AAP)