Suchergebnisse

The rise in the prevalence of autoimmune diseases in developed societies has been associated with a change in lifestyle patterns. Among other factors, increased consumption of certain dietary components, such as table salt and fatty acids and excessive caloric intake has been associated with defective immunological tolerance. Dietary nutrients have shown to modulate the immune response by a direct effect on the function of immune cells or, indirectly, by acting on the microbiome of the gastrointestinal tract. FOXP3(+) regulatory T cells (Tregs) suppress immune responses and are critical for maintaining peripheral tolerance and immune homeostasis, modulating chronic tissue inflammation and autoimmune disease. It is now well-recognized that Tregs show certain degree of plasticity and can gain effector functions to adapt their regulatory function to different physiological situations during an immune response. However, plasticity of Tregs might also result in conversion into effector T cells that may contribute to autoimmune pathogenesis. Yet, which environmental cues regulate Treg plasticity and function is currently poorly understood, but it is of significant importance for therapeutic purposes. Here we review the current understanding on the effect of certain dietary nutrients that characterize Western diets in Treg metabolism, stability, and function. Moreover, we will discuss the role of Tregs linking diet and autoimmunity and the potential of dietary-based interventions to modulate Treg function in disease. ; MK was supported by the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program (640116), by a SALK-grant from the government of Flanders, Belgium and by an Odysseus-grant of the Research Foundation Flanders (FWO), Belgium. ; Kleinewietfeld, M (reprint author), Univ Hasselt, VIB Lab Translat Immunomodulat, VIB Ctr Inflammat Res IRC, Hasselt, Belgium. markus.kleinewietfeld@uhasselt.vib.be

Dietary habits are amongst the main factors that influence the gut microbiome. Accumulating evidence points to the impact of a high-salt diet (HSD) on the composition and function of the intestinal microbiota, immune system and disease. In the present study, we thus investigated the effects of different NaCl content in the food (0.03%/sodium deficient, 0.5%/control, 4% and 10% NaCl) on the gut microbiome composition in mice. The bacterial composition was profiled using the 16S ribosomal RNA (rRNA) gene amplicon sequencing. Our results revealed that HSD led to distinct gut microbiome compositions compared to sodium-deficient or control diets. We also observed significant reduction in relative abundances of bacteria associated with immuno-competent short-chain fatty acid (SCFA) production (Bifidobacterium, Faecalibaculum, Blautia and Lactobacillus) in HSD-fed mice along with significant enrichment of Clostridia, Alistipes and Akkermansia depending on the sodium content in food. Furthermore, the predictive functional profiling of microbial communities indicated that the gut microbiota found in each category presents differences in metabolic pathways related to carbohydrate, lipid and amino acid metabolism. The presented data show that HSD cause disturbances in the ecological balance of the gastrointestinal microflora primarily through depletion of lactic acid-producing bacteria in a dose-dependent manner. These findings may have important implications for salt-sensitive inflammatory diseases. ; A.C. was supported by a Ph.D. fellowship (11L8322N) of the Research Foundation Flanders, Belgium (FWO). M.K. was supported by the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program (640116) and by a SALK-grant from the government of Flanders and by an Odysseus-grant (G0G1216) and research project (G080121N) of the FWO. M.K. and J.V. were supported by a BOF grant (ADMIRE) from Hasselt University.

FOXP3(+) regulatory T cells (Tregs) are central for maintaining peripheral tolerance and immune homeostasis. Because of their immunosuppressive characteristics, Tregs are a potential therapeutic target in various diseases such as autoimmunity, transplantation and infectious diseases like COVID-19. Numerous studies are currently exploring the potential of adoptive Treg therapy in different disease settings and novel genome editing techniques like CRISPR/Cas will likely widen possibilities to strengthen its efficacy. However, robust and expeditious protocols for genome editing of human Tregs are limited. Here, we describe a rapid and effective protocol for reaching high genome editing efficiencies in human Tregs without compromising cell integrity, suitable for potential therapeutic applications. By deletion of IL2RA encoding for IL-2 receptor alpha-chain (CD25) in Tregs, we demonstrated the applicability of the method for downstream functional assays and highlighted the importance for CD25 for in vitro suppressive function of human Tregs. Moreover, deletion of IL6RA (CD126) in human Tregs elicits cytokine unresponsiveness and thus may prevent IL-6-mediated instability of Tregs, making it an attractive target to potentially boost functionality in settings of adoptive Treg therapies to contain overreaching inflammation or autoimmunity. Thus, our rapid and efficient protocol for genome editing in human Tregs may advance possibilities for Treg-based cellular therapies. ; European Research Council (ERC) under the European Union [640116]; SALK-grant from the government of Flanders; Research Foundation Flanders, Belgium (FWO)

Excess salt intake could affect the immune system by shifting the immune cell balance toward a pro-inflammatory state. Since this shift of the immune balance is thought to be beneficial in anti-cancer immunity, we tested the impact of high salt diets on tumor growth in mice. Here we show that high salt significantly inhibited tumor growth in two independent murine tumor transplantation models. Although high salt fed tumor-bearing mice showed alterations in T cell populations, the effect seemed to be largely independent of adaptive immune cells. In contrast, depletion of myeloid-derived suppressor cells (MDSCs) significantly reverted the inhibitory effect on tumor growth. In line with this, high salt conditions almost completely blocked murine MDSC function in vitro. Importantly, similar effects were observed in human MDSCs isolated from cancer patients. Thus, high salt conditions seem to inhibit tumor growth by enabling more pronounced anti-tumor immunity through the functional modulation of MDSCs. Our findings might have critical relevance for cancer immunotherapy. ; MKi was supported by a Ph.D. grant from the Research Foundation Flanders (FWO), Belgium. MKl was supported by the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program (640116), by a SALK-grant from the government of Flanders, Belgium and by an Odysseus-grant of the FWO, Belgium.