Tolerogenic dendritic cells (tolDC) play an essential role in regulating immune response by inducing an effective Treg response, especially those obtained with IL10-based protocol. Recently tolDC have become a relevant subject due to their ability to regulate immune response under different conditions like autoimmune diseases and food allergies.
In order to characterize tolDC that exhibit a robust Treg induction, we built a logical model of their tolerization using IL10, by integrating published knowledge, transcriptome data, and identification of transcription factor binding sites (TFBS).
We first performed a literature search in PubMed and found several papers that were included in our model. We then performed a gene expression analysis of the available transcriptome data in GEO (GSE117946). Based on our gene expression analysis, we identified five differentially expressed transcription factors (TFs), IRF8, TCF7L2, GAL4, CEBPB, and TFCP2L1, in tolDC had not been related before to tolDC obtention. Using JASPAR (Castro-Mondragon et al. 2022) matrices for these TFs we searched for TFBS in the upstream region of genes related to the tolerogenic phenotype in tolDC obtained using IL10 protocol. Once we predicted TFBS in the interested genes, those new predicted regulations were used to complete our model.
Our logical model integrates differential gene expresión, predicted transcription factor binding sites, and current knowledge about IL10 signaling in monocytes-derived dendritic cells (moDC). With our completed model we performed in silico mutants of the TFs involved (STAT3, STAT6, IRF8, TCF7L2, GAL4, CEBPB, and TFCP2L1), consistent with current knowledge of the STAT6, CEBPB, and IRF8 mutants, in the presence of IL10, allow for the expression of tolerogenic specific gene markers. On the contrary STAT3, TCF7L2, and TFCP2L1 mutants, in the presence of IL10, abolished the tolerogenic specific gene markers.
The novelty of our study is the identification of the role of TFs that had not been described as involved in the tolerization of dendritic cells. Our model helps understand the differences in gene expression when IL10 is used to obtain tolDC and could be used as a base to integrate other tolerogenic protocols and be able to contrast the basal behavior with immune diseases.