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Strain specific maturation of dendritic cells and production of IL-1β controls CD40-driven colitis
Ogrinc Wagner, A ; Friedrich, V ; Barthels, C ; Marconi, P ; Blutke, A ; Brombacher, F ; Brocker, T
Ogrinc Wagner, A
Friedrich, V
Barthels, C
Marconi, P
Blutke, A
Brombacher, F
Brocker, T
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Abstract
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-γ+IL-17+ Th17 cells and IFN-γ+ 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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2019-01-17
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PLoS One
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Ogrinc Wagner A, Friedrich V, Barthels C, Marconi P, Blutke A, Brombacher F, Brocker T. Strain specific maturation of Dendritic cells and production of IL-1β controls CD40-driven colitis. PLoS One. 2019 Jan 17;14(1):e0210998. doi: 10.1371/journal.pone.0210998.