Defective Differentiation of Regulatory FoxP3+ T Cells by Small-Intestinal Dendritic Cells in Patients With Type 1 Diabetes

Abstract

OBJECTIVEThe gut environment modulates the pathogenesis of type 1 diabetes (T1D), but how it affects autoimmunity toward pancreatic β-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 METHODSWe 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, γδ 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.RESULTSOur 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.CONCLUSIONSOur 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 β-cells and preventing T1D.

Early life treatment with vancomycin propagates Akkermansia muciniphila and reduces diabetes incidence in the NOD mouse

“…As such, induction of different subsets of Tregs could be a possible commensal-regulated immune pathway involved in protection from diabetes [38]. Nonetheless, we found no differences among Treg and tolerogenic DC populations in either mucosal or systemic compartments after vancomycin treatment.…”

Mode of Delivery Shapes Gut Colonization Pattern and Modulates Regulatory Immunity in Mice

“…Consistent with this, defective Tregs have been suggested to explain the imbalance of T lymphocyte subsets found in T1D patients (26)(27)(28). Dysfunctional tolerogenic dendritic cells (DCs) and a reduced percentage of Foxp3 + Tregs in the gut of T1D patients support the notion that the mucosal immune system, in parallel with the early gut microbiota, plays an important role in the pathogenesis (29).…”

Gut microbial markers are associated with diabetes onset, regulatory imbalance, and IFN-γ level in NOD Mice

“…25,26 In addition, jejunal biopsies from T1D patients showed reduced frequency of FoxP3 C Treg cells and CD103 C tolerogenic DCs defective of inducing FoxP3 C Treg cell differentiation. 27 We therefore propose that a microbiota signature characterized by a decrease in S24-7, Bacteriodales, and Prevotella and an increase in Lachnospiraceae, Ruminococcus, and Oscillospira may contribute to the pathogenesis of T1D by decreasing FoxP3 C Treg cells that protects against diabetes. OTUs classified to S24-7 seem to be largely unexplored in mice models for the time being.…”