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.
Highlights
FoxP3+ regulatory T cells (Tregs) control immune responses and maintain homeostatic immunological balance in many tissues and organs [1]
CD40-signalling is involved in colitis and inflammatory bowel disease (IBD) and we show in the present study that the role for CD40-signaling in colitis depends on strain variations
Only B6DC-LMP1/CD40-mice showed all signs of inflammation and colitis as published previously [15], while neither F1 nor B/c mice developed colitis, nor did they show signs of inflammatory cytokine production
Summary
FoxP3+ regulatory T cells (Tregs) control immune responses and maintain homeostatic immunological balance in many tissues and organs [1]. Tregs can develop in the thymus as natural regulatory T cells (nTregs) or in peripheral tissues by differentiation from mature CD4+ T cells to induced Tregs (iTregs) [2]. This latter process requires transforming growth factor β. Role of genetic background in colitis (TGFβ) as well as the presence of microbiota [3]. ITregs occur mainly in intestinal tissues, where Dendritic cells (DCs) present dietary and commensal antigens and play a central role in mucosal homeostasis [4]. Microbiota induce expression of retinoic acid receptor-related orphan γt (RORγt) in iTregs [5, 6]. The deletion of iTregs caused increased production of inflammatory cytokines and raised the susceptibility of mice to develop inflammatory bowel disease (IBD) [5, 6]
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