Logical model of human tolerogenic dendritic cells and their participation in autoimmune disease

Abstract

AbstractTolerogenic dendritic cells (tolDC) regulate the immune response, several clinical trials focused on autoimmune diseases use tolDC to promote immune tolerance response and Treg activation. Here we built a logical model for the tolerization cellular process of dendritic cells using IL10. By combining literature knowledge, microarray gene expression, and key tolDC markers, we ensembled a logical model that describes the obtention of tolDC using the IL10 signaling cascade that spawns the most tolerogenic phenotype. The model uses IL10 as input and the signaling cascade that trigger seven transcription factors (TFs), three previously known TFs in the IL10 response (STAT3, NFKB, STAT6), and four were incorporated based on our gene expression analysis (IRF8, TCF7L2, CEBPB, and TFCP2L1). Using our model, we generated mutantsin-silicoand identified that even when IL10 is present the single mutants for TCF7L2, IRF8, TFCP2L1, and STAT3 were not able to reach a tolDC stable state, highlighting the relevance of these TFs in the process. The current model sets a precedent that will help in the development of tolDC for future applications.