Dendritic Cells Control Regulatory T Cell Function Required for Maintenance of Intestinal Tissue Homeostasis

Abstract

Dendritic cells (DCs) together with regulatory T cells (Tregs) are essential mediators of immune homeostasis. Disruption of function or frequency of either cell type can lead to fatal autoimmunity. We previously described that mice constitutively lacking DCs (ΔDC) develop autoimmunity characterized by reduced body weight, autoantibodies, and pronounced intestinal inflammation. In this study, we show that lack of DCs leads to an altered gene expression profile in peripheral but not thymic Tregs with increased expression of inhibitory receptors. The suppressive function of Tregs from DDC mice was impaired in T cell cocultures. In a model of transfer colitis, Tregs from ΔDC mice were only functional in the presence of DCs in recipient mice. Lack of MHC class II on DCs also resulted in upregulation of inhibitory receptors on Tregs, reduced body weight, and elevated serum IgA levels. Further analysis of the IgA response revealed an expansion of IgA + germinal center B cells and plasma cells in mesenteric lymph nodes and more IgA-coated commensal bacteria in feces of ΔDC mice. Thus, we show a critical role for DCs to establish intestinal homeostasis by regulating Treg function for prevention of spontaneous inflammation.

Targeted 1H NMR metabolomics and immunological phenotyping of human fresh blood and serum samples discriminate between healthy individuals and inflammatory bowel disease patients treated with anti-TNF

“…Antigen-presenting cells (APC), such as dendritic cells (DC) or intestinal epithelial cells, are able to sense the extra-luminal environment and cooperate with the gut adaptive immune system to maintain a tolerogenic response by activation of the CD4 + T regulatory subset, expressing forkhead box P3 (FoxP3) transcription factor, and thereby secreting interleukin-10 into the gut lamina propria . In IBD pathogenesis, crosstalk between the gut immune system cells and the microbiota is altered, leading to the disruption of the gut barrier and translocation of microbiota to the lamina propria that triggers Th1/Th2 and Treg/Th17 imbalance that culminates in chronic inflammation [ 2 ]. Aberrant T cell activation and proliferation are one of the mechanisms responsible for IBD, where high amounts of pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α), interleukin-17 (IL-17), or interferon-γ (IFN-γ) are released in the gut epithelium by activated Th1, or Th17 [ 3 ].…”

Host Factors in Dysregulation of the Gut Barrier Function during Alcohol-Associated Liver Disease

“…They then processed antigens to T cells and B cells in the mucosa or in organized secondary lymphoid structures known as Peyer’s Patches, as well as in mesenteric lymph nodes [ 46 ]. Tolerogenic dendritic cells promote differentiation of regulatory T cells (Treg) [ 47 ], which in turn are able to induce tolerogenic DCs via IL-10, TGF-β, and other surface molecules [ 48 ]. DCs in gut-associated lymphoid tissue (GALT) and mesenteric lymph nodes further promote differentiation of B cells into immunoglobulin A (IgA)-producing plasma cells and memory B cells.…”

Centrality of Myeloid-Lineage Phagocytes in Particle-Triggered Inflammation and Autoimmunity

“…Furthermore, specific DC subsets secrete type I IFN and B-cell activating factor (BAFF), which regulate B cell differentiation into antibody-secreting plasma cells ( Jego et al, 2005 ). Intriguingly, DCs also can promote and maintain immunological tolerance by inducing regulatory T cell (Treg) differentiation through cell-to-cell contact or secreted cytokines such as TGF-β and IL-10 ( Raker et al, 2015 ; Hilpert et al, 2019 ). Consequently, activated Tregs can suppress proliferation and differentiation of naïve T cells into effector T cells, as well as the functions of activated CD4 + and CD8 + T cells, B cells, macrophages, and DCs.…”