GSE134874
RNA-seq analysis of immune responses from human blood monocyte dendritic cells from 3 donors stimulated with 5 pattern recognition receptor (PRR) ligands along with their pairwise and triplet combinations
The immune system makes decisions in response to combinations of multiple microbial inputs. We do not understand the combinatorial logic governing how higher-order combinations of microbial signals shape immune responses. Here, using coculture experiments and statistical analyses, we discover a general property for the combinatorial sensing of microbial signals, whereby the effects of triplet combinations of microbial signals on immune responses can be predicted by combining the effects of single and pairs. Mechanistically, we find that singles and pairs dictate the information signaled by triplets in mouse and human DCs at the levels of transcription, chromatin and protein secretion. We exploit this simplifying property to develop cell-based immunotherapies prepared with adjuvant combinations that trigger protective responses in mouse models of cancer. We conclude that the processing of multiple input signals by innate immune cells is governed by pairwise effects, which will inform the rationale combination of adjuvants to manipulate immunity. Overall design: mRNA expression profiles of human monocytes derived dendritic cells from three independent donors stimulated with five PRR ligands in singles, their pair and triplet combinations generated by RNA-seq in triplicates using illumina nextseq 550