Abstract
BackgroundDefects in APC and regulatory cells are associated with diabetes development in NOD mice. We have shown previously that NOD APC are not effective at stimulating CD4+CD25+ regulatory cell function in vitro. We hypothesize that failure of NOD APC to properly activate CD4+CD25+ regulatory cells in vivo could compromise their ability to control pathogenic cells, and activation of NOD APC could restore this defect, thereby preventing disease.Methodology/Principal FindingsTo test these hypotheses, we used the well-documented ability of complete Freund's adjuvant (CFA), an APC activator, to prevent disease in NOD mice. Phenotype and function of CD4+CD25+ regulatory cells from untreated and CFA-treated NOD mice were determined by FACS, and in vitro and in vivo assays. APC from these mice were also evaluated for their ability to activate regulatory cells in vitro. We have found that sick NOD CD4+CD25+ cells expressed Foxp3 at the same percentages, but decreased levels per cell, compared to young NOD or non-NOD controls. Treatment with CFA increased Foxp3 expression in NOD cells, and also increased the percentages of CD4+CD25+Foxp3+ cells infiltrating the pancreas compared to untreated NOD mice. Moreover, CD4+CD25+ cells from pancreatic LN of CFA-treated, but not untreated, NOD mice transferred protection from diabetes. Finally, APC isolated from CFA-treated mice increased Foxp3 and granzyme B expression as well as regulatory function by NOD CD4+CD25+ cells in vitro compared to APC from untreated NOD mice.Conclusions/SignificanceThese data suggest that regulatory T cell function and ability to control pathogenic cells can be enhanced in NOD mice by activating NOD APC.
Highlights
Dysregulation of the immune response in NOD mice plays a major role in the induction of type 1 diabetes [1,2]
We speculated that NOD antigen-presenting cells (APC) may exhibit a similar defect in vivo in NOD mice, which may be reflected by lower Foxp3 expression in CD4+CD25+ cells
Our previous study suggested that defects in NOD APC could be directly responsible for the lower functional activity of CD4+CD25+ regulatory T cells in NOD mice [16]
Summary
Dysregulation of the immune response in NOD mice plays a major role in the induction of type 1 diabetes [1,2]. It is well established that CD4+CD25+ regulatory T cells, which account for 5–10% of CD4+ cells in healthy mice and humans, control the development of many autoimmune diseases. Their mechanisms of action are still controversial [8], these cells absolutely require activation [9,10], presumably by APC, to function in vitro and probably in vivo. Studies using transgenic mice expressing GFP under control of the Foxp promoter has confirmed the relationship between Foxp and regulatory cell function [8,14]. Defects in APC and regulatory cells are associated with diabetes development in NOD mice. We hypothesize that failure of NOD APC to properly activate CD4+CD25+ regulatory cells in vivo could compromise their ability to control pathogenic cells, and activation of NOD APC could restore this defect, thereby preventing disease
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