Abstract
The use of autologous tolerogenic dendritic cells (tolDC) has become a promising alternative for the treatment of autoimmune diseases. Among the different strategies available, the use of vitamin D3 for the generation of tolDC (vitD3-tolDC) constitutes one of the most robust approaches due to their immune regulatory properties, which are currently being tested in clinical trials. However, the mechanisms that vitD3-tolDC trigger for the induction of tolerance remain elusive. For this reason, we performed a full phenotypical, functional, and transcriptomic characterization of T cells upon their interaction with autologous, antigen-specific vitD3-tolDC. We observed a strong antigen-specific reduction of T cell proliferation, combined with a decrease in the relative prevalence of TH1 subpopulations and IFN-γ production. The analysis of the transcriptomic profile of T CD4+ cells evidenced a significant down-modulation of genes involved in cell cycle and cell response to mainly pro-inflammatory immune-related stimuli, highlighting the role of JUNB gene as a potential biomarker of these processes. Consequently, our results show the induction of a strong antigen-specific hyporesponsiveness combined with a reduction on the TH1 immune profile of T cells upon their interaction with vitD3-tolDC, which manifests the regulatory properties of these cells and, therefore, their therapeutic potential in the clinic.
Highlights
In the last years, tolerogenic dendritic cells have become one of the most promising alternatives for the treatment of autoimmune diseases, such as multiple sclerosis (MS), rheumatoid arthritis, or type 1 diabetes
Here we present a full phenotypical, functional, and transcriptomic characterization of T CD4+ cells after their interaction with autologous vitD3-tolerogenic dendritic cells (tolDC) loaded with tetanus toxin (TT), in order to study the antigen-specific effect mediated by these cells compared to TT-loaded immunogenic mature DC (mDC)
The purpose of this study is to identify one or several potential biomarkers of the immune modulation developed by vitD3-tolDC over T cells, which could constitute an interesting tool for the monitoring of patients treated with these cells in clinical trials, and the understanding of the mechanisms of tolerance induction
Summary
Tolerogenic dendritic cells (tolDC) have become one of the most promising alternatives for the treatment of autoimmune diseases, such as multiple sclerosis (MS), rheumatoid arthritis, or type 1 diabetes. TolDC are commonly defined as a stable and semi-mature subset of dendritic cells (DC), VitD3-tolDC Induce T-Cell Transcriptomic Hyporresponsiveness between antigen-capturing immature DC (iDC) and immunogenic mature DC (mDC)—characterized by their increased expression of MHC class II and co-stimulatory molecules. A wide variety of protocols for their production have been reported, ranging from the use of different drugs and chemical agents to genetic engineering techniques [6, 7]. In this regard, the use of 1,25-dyhydroxyvitamin D3, the active form of vitamin D3, constitutes one of the most widely studied approaches for the differentiation of tolDC. VitD3-tolDC are characterized by a reduced NF-kB-mediated activity and an increase of mTOR-mediated glucose metabolism [10, 19]
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