Strain specific maturation of Dendritic cells and production of IL-1[beta] controls CD40-driven colitis

Intestinal integrity is maintained by balanced numbers of CD103.sup.+ 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.sup.+ DCs in the lamina propria...

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Published inPloS one Vol. 14; no. 1; p. e0210998
Main Authors Ogrinc Wagner, Ana, Friedrich, Verena, Barthels, Christian, Marconi, Peggy, Blutke, Andreas, Brombacher, Frank, Brocker, Thomas
Format Journal Article
LanguageEnglish
Published Public Library of Science 17.01.2019
Subjects
Colitis
Dendritic cells
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Summary:Intestinal integrity is maintained by balanced numbers of CD103.sup.+ 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.sup.+ 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.sup.+ DCs in B6, but reduced in F1 and diminished in B/c background. We further show direct correlation of CD103.sup.+ 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].sup.+ IL-17.sup.+ Th17 cells and IFN-[gamma].sup.+ 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.sup.+ DC/iTreg-axis to tip intestinal homeostatic balance to pathology.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0210998