Defective FoxP3+ Treg cell differentiation in the gut of Type 1 Diabetic patients

Environmental factors that act at the intestinal level such as diet, drugs, and microflora have a high impact on the pathogenesis of autoimmune Type 1 Diabetes (T1D), but it is still unclear how the gut milieu affects autoimmunity outside the intestine. Here we show that peripheral FoxP3+ Treg cell differentiation, a mechanism that takes place in the gut and is crucial to maintain systemic immune tolerance, is impaired in T1D patients. These results provide the first evidence that gut mucosa alteration could predispose to autoimmune T1D by affecting systemic immune regulation

Commensal Bacteria-Specific CD4+ T Cell Responses in Health and Disease

Over the course of evolution, mammalian body surfaces have adapted their complex immune system to allow a harmless coexistence with the commensal microbiota. The adaptive immune response, in particular CD4+ T cell-mediated, is crucial to maintain intestinal immune homeostasis by discriminating between harmless (e.g., dietary compounds and intestinal microbes) and harmful stimuli (e.g., pathogens). To tolerate food molecules and microbial components, CD4+ T cells establish a finely tuned crosstalk with the environment whereas breakdown of these mechanisms might lead to chronic disease associated with mucosal barriers and beyond. How commensal-specific immune responses are regulated and how these molecular and cellular mechanisms can be manipulated to treat chronic disorders is yet poorly understood. In this review, we discuss current knowledge of the regulation of commensal bacteria-specific CD4+ T cells. We place particular focus on the key role of commensal-specific CD4+ T cells in maintaining tolerance while efficiently eradicating local and systemic infections, with a focus on factors that trigger their aberrant activation

Increased iNKT17 Cell Frequency in the Intestine of Non-Obese Diabetic Mice Correlates With High Bacterioidales and Low Clostridiales Abundance

iNKT cells play different immune function depending on their cytokine-secretion phenotype. iNKT17 cells predominantly secrete IL-17 and have an effector and pathogenic role in the pathogenesis of autoimmune diseases such as type 1 diabetes (T1D). In line with this notion, non-obese diabetic (NOD) mice that spontaneously develop T1D have an increased percentage of iNKT17 cells compared to non-autoimmune strains of mice. The factors that regulate iNKT cell expansion and acquisition of a specific iNKT17 cell phenotype are unclear. Here, we demonstrate that the percentage of iNKT17 cells is increased in the gut more than peripheral lymphoid organs of NOD mice, thus suggesting that the intestinal environment promotes iNKT17 cell differentiation in these mice. Increased intestinal iNKT17 cell differentiation in NOD mice is associated with the presence of pro-inflammatory IL-6-secreting dendritic cells that could contribute to iNKT cell expansion and iNKT17 cell differentiation. In addition, we found that increased iNKT17 cell differentiation in the large intestine of NOD mice is associated with a specific gut microbiota profile. We demonstrated a positive correlation between percentage of intestinal iNKT17 cells and bacterial strain richness (α-diversity) and relative abundance of Bacterioidales strains. On the contrary, the relative abundance of the anti-inflammatory Clostridiales strains negatively correlates with the intestinal iNKT17 cell frequency. Considering that iNKT17 cells play a key pathogenic role in T1D, our data support the notion that modulation of iNKT17 cell differentiation through gut microbiota changes could have a beneficial effect in T1D

Perfluorooctanesulfonic acid modulates barrier function and systemic T cell homeostasis during intestinal inflammation.

The intestinal epithelium is continuously exposed to deleterious environmental factors which might cause aberrant immune responses leading to inflammatory disorders. However, what environmental factors might contribute to disease are yet poorly understood. Here, to overcome the lack of in vivo models suitable for screening of environmental factors we used zebrafish reporters of intestinal inflammation. Using zebrafish, we interrogated the immunomodulatory effects of polyfluoroalkyl substances (PFAS), which have been positively associated with ulcerative colitis incidence. Exposure with perfluorooctanesulfonic acid (PFOS) during TNBS-induced inflammation enhances the expression of proinflammatory cytokines as well as neutrophil recruitment to the intestine of zebrafish larvae, which was validated in TNBS-induced colitis mice models. Moreover, PFOS exposure in mice undergoing colitis resulted in neutrophil-dependent increased intestinal permeability and enhanced PFOS translocation into circulation. Finally, this was associated with a neutrophil dependent expansion of systemic CD4+ T cells. Thus, our results indicate that PFOS worsens inflammation-induced intestinal damage with disruption of T cell homeostasis beyond the gut and provides a novel in vivo toolbox to screen for pollutants affecting intestinal homeostasis

Oral Probiotic VSL#3 Prevents Autoimmune Diabetes by Modulating Microbiota and Promoting Indoleamine 2,3-Dioxygenase-Enriched Tolerogenic Intestinal Environment

The gut microbiota modulates the autoimmune pathogenesis of type 1 diabetes (T1D) via mechanisms that remain largely unknown. The inflammasome components are innate immune sensors that are highly influenced by the gut environment and play pivotal roles in maintaining intestinal immune homeostasis. In this study we show that modifications of the gut microbiota induced by oral treatment with Lactobacillaceae-enriched probiotic VSL#3, alone or in combination with retinoic acid (RA), protect NOD mice from T1D by affecting inflammasome at the intestinal level. In particular, we show that VSL#3 treatment inhibits IL-1β expression while enhancing release of protolerogenic components of the inflammasome, such as indoleamine 2,3-dioxygenase (IDO) and IL-33. Those modifications of the intestinal microenvironment in VSL#3-treated NOD mice modulate gut immunity by promoting differentiation of tolerogenic CD103+ DCs and reducing differentiation/expansion of Th1 and Th17 cells in the intestinal mucosa and at the sites of autoimmunity, that is, within the pancreatic lymph nodes (PLN) of VSL#3-treated NOD mice. Our data provide a link between dietary factors, microbiota composition, intestinal inflammation, and immune homeostasis in autoimmune diabetes and could pave the way for new therapeutic approaches aimed at changing the intestinal microenvironment with probiotics to counterregulate autoimmunity and prevent T1D

data_sheet_1_Increased iNKT17 Cell Frequency in the Intestine of Non-Obese Diabetic Mice Correlates With High Bacterioidales and Low Clostridiales Abundance.PDF

<p>iNKT cells play different immune function depending on their cytokine-secretion phenotype. iNKT17 cells predominantly secrete IL-17 and have an effector and pathogenic role in the pathogenesis of autoimmune diseases such as type 1 diabetes (T1D). In line with this notion, non-obese diabetic (NOD) mice that spontaneously develop T1D have an increased percentage of iNKT17 cells compared to non-autoimmune strains of mice. The factors that regulate iNKT cell expansion and acquisition of a specific iNKT17 cell phenotype are unclear. Here, we demonstrate that the percentage of iNKT17 cells is increased in the gut more than peripheral lymphoid organs of NOD mice, thus suggesting that the intestinal environment promotes iNKT17 cell differentiation in these mice. Increased intestinal iNKT17 cell differentiation in NOD mice is associated with the presence of pro-inflammatory IL-6-secreting dendritic cells that could contribute to iNKT cell expansion and iNKT17 cell differentiation. In addition, we found that increased iNKT17 cell differentiation in the large intestine of NOD mice is associated with a specific gut microbiota profile. We demonstrated a positive correlation between percentage of intestinal iNKT17 cells and bacterial strain richness (α-diversity) and relative abundance of Bacterioidales strains. On the contrary, the relative abundance of the anti-inflammatory Clostridiales strains negatively correlates with the intestinal iNKT17 cell frequency. Considering that iNKT17 cells play a key pathogenic role in T1D, our data support the notion that modulation of iNKT17 cell differentiation through gut microbiota changes could have a beneficial effect in T1D.</p

Defective differentiation of regulatory FoxP3+ T cells by small-intestinal dendritic cells in patients with type 1 diabetes

OBJECTIVE: The gut environment modulates the pathogenesis of type 1 diabetes (T1D), but how it affects autoimmunity toward pancreatic beta-cells, a self-tissue located outside the intestine, is still unclear. In the small intestine, lamina propria dendritic cells (LPDCs) induce peripheral differentiation of FoxP3(+) regulatory T (Treg) cells. We tested the hypothesis that the intestinal milieu impinges on human T1D by affecting differentiation of FoxP3(+) Treg cells. RESEARCH DESIGN AND METHODS: We collected duodenal biopsies of 10 T1D patients, 16 healthy subjects, and 20 celiac individuals and performed a fluorescent-activated cell sorter analysis to measure percentages of various immune cell subsets, including CD4(+) and CD8(+) T cells, NK cells, gammadelta T cells, CD103(+)CD11c(+) LPDCs, and CD4(+)CD25(+)FoxP3(+)CD127(-) Treg cells. In parallel, we assessed the tolerogenic function (i.e., capacity to induce differentiation of FoxP3(+) Treg cells) by LPDCs of T1D patients and control subjects. RESULTS: Our analysis revealed a significant reduction in the percentage of intestinal CD4(+)CD25(+)FoxP3(+)CD127(-) Treg cells in T1D patients compared with healthy subjects (P = 0.03) and celiac individuals (P = 0.003). In addition, we found that LPDCs from T1D patients completely lacked their tolerogenic function; they were unable to convert CD4(+)CD25(-) T cells into CD4(+)CD25(+)FoxP3(+)CD127(-) Treg cells. CONCLUSIONS: Our data indicate that T1D patients have a reduced number of intestinal FoxP3(+) Treg cells as a result of their defective differentiation in the gut. These findings suggest that intestinal immune regulation is not only calibrated to tolerate commensal bacteria and food components but also is instrumental in maintaining immune tolerance toward pancreatic beta-cells and preventing T1D