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RNA-seq analysis of immune responses from mouse bone marrow derived dendritic cells stimulated with 7 pattern recognition receptor (PRR) ligands along with their pairwise and triplet combinations

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE134869 | GEO | 2020/07/01

REPOSITORIES: GEO

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Project description:The physiological function of the immune system and the response to therapeutic immunomodulators may be sensitive to combinatorial cytokine micro-environments that shape the responses of specific immune cells. Previous work shows that paracrine cytokines released by virus-infected human dendritic cells (DC) can dictate the maturation state of naM-CM-/ve DCs. To understand the effects of paracrine signaling, we systematically studied the effects of combinations cytokines in this complex mixture in generating an antiviral state. After naM-CM-/ve DCs were exposed to either IFNM-NM-2 or to paracrine signaling released by DCs infected by Newcastle Disease Virus (NDV), microarray analysis revealed a large number of genes that were differently regulated by the DC-secreted paracrine signaling. In order to identify the cytokine mechanisms involved, we identified 20 cytokines secreted by NDV infected DCs for which the corresponding receptor gene is expressed in naM-CM-/ve DCs. By exposing cells to all combinations of 19 cytokines (leave-one-out studies) we identified 5 cytokines (IFNM-NM-2, TNFM-NM-1, IL-1M-oM-^AM-", TNFSF15 and IL28) as candidates for regulating DC maturation markers. Subsequent experiments identified IFNM-NM-2, TNFM-NM-1 and IL1M-oM-^AM-" as the major synergistic contributors to this antiviral state. This finding was supported by infection studies in vitro, by T cell activation studies and by in vivo infection studies in mouse. Combination of cytokines can cause response states in DCs that differ from those achieved by the individual cytokines alone. These results suggest that the cytokine microenvironment may act via a combinatorial code to direct the response state of specific immune cells. Further elucidation of this code may provide insight into responses to infection and neoplasia as well as guide the development of combinatorial cytokine immunomodulation for infectious, autoimmune and immunosurveillance-related diseases. Cells exposed to the supernatant of NDV infected cells were compared to NDV infected cells, IFNM-NM-2 treated cells and naM-CM-/ve dendritic cells after 8 hours.

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RNA-seq analysis of immune responses from mouse bone marrow derived dendritic cells stimulated with 7 pattern recognition receptor (PRR) ligands along with their pairwise and triplet combinations

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