On the other hand, defects in CD4+ Regulatory T cell (Treg) numbers and/or function contribute to T1D aetiology in NOD mice and in humans. In this work, we formally tested whether the protective role of the bacterial product lipopolysaccharide (LPS) on diabetes incidence results from enhanced Treg activity. We first report that weekly administration of LPS selleck chemicals llc to young prediabetic NOD mice, presenting or not insulitis at the time of treatment, afforded full protection from diabetes. Taking advantage from the high but incomplete penetrance of diabetes in NOD mice raised in specific pathogen free (SPF) conditions we compared untreated disease-free old animals with gender- and age-matched LPS-treated mice. Histological

and flow cytometry analysis indicated that LPS treatment did not prevent islet infiltration or priming of diabetogenic T cells but increased Foxp3+ and CD103+ Treg frequency and numbers. By performing adoptive transfer experiments into alymphoid NOD/SCID recipients, we further demonstrated that CD25+ cells from LPS-treated NOD mice, but not from naturally protected animals, maintained diabetogenic cells at check. Our study suggests that T cell regulation represents a cellular mechanism to explain the ‘hygiene hypothesis’ and reinforces the notion that immune activity consolidates dominant tolerance. The non-obese diabetic (NOD) mouse develops spontaneous autoimmune diabetes that closely resembles the human type

I diabetes (T1D) pathology. Beta cell destruction in NOD mice is T cell dependent and leads to impaired insulin production and consequently NVP-LDE225 order diabetes. Pancreatic islet inflammation is initiated around 3 weeks of age with infiltration by DC and macrophages, followed by the recruitment of lymphocytes. Despite extensive infiltration of the pancreatic islets, disease remains clinically silent for about another 12 weeks. GPX6 The observation that insulitis precedes diabetes by many weeks suggests that dominant regulatory mechanisms control disease progression. Several cell subsets were implicated in diabetes regulation, among which NK T and CD4+

Regulatory T cells (Treg) are the best studied [1]. NOD mice have lower number of Treg as compared with non-autoimmune mouse strains [2, 3]. Moreover, Treg in NOD animals undergo progressive loss of function with age [4–7]. In addition, analysis of T1D patients revealed decreased number [8] or functionally deficient Treg [9], when compared with healthy individuals. Hence, Treg alterations appear to take part of the aetiology of T1D in mice and in humans. Evidence that Treg are directly involved in limiting diabetes progression in mice, rats and humans is solid. Foxp3-deficient NOD mice exhibit increased incidence and earlier onset of diabetes as compared to WT NOD mice [10]. Moreover, monoclonal antibody (mAb)-mediated IL-2 neutralization, a protocol that decreases Treg numbers, precipitates diabetes in NOD mice [11] while IL-2 treatment prevents disease [12].