Transcriptomic Analysis Identifies A Tolerogenic Dendritic Cell Signature

Abstract

Dendritic cells (DC) are central to regulating innate and adaptive immune responses. Strategies that modify DC function provide new therapeutic opportunities in autoimmune diseases and transplantation. Current pharmacological approaches can alter DC phenotype to induce tolerogenic DC (tolDC), a maturation-resistant DC subset capable of directing a regulatory immune response that are being explored in current clinical trials. The classical phenotypic characterization of tolDC is limited to cell-surface marker expression and anti-inflammatory cytokine production, although these are not specific. TolDC may be better defined using gene signatures, but there is no consensus definition regarding genotypic markers. We address this shortcoming by analyzing available transcriptomic data to yield an independent set of differentially expressed genes that characterize human tolDC. We validate this transcriptomic signature and also explore gene differences according to the method of tolDC generation. As well as establishing a novel characterization of tolDC, we interrogated its translational utility in vivo, demonstrating this geneset was enriched in the liver, a known tolerogenic organ. Our gene signature will potentially provide greater understanding regarding transcriptional regulators of tolerance and allow researchers to standardize identification of tolDC used for cellular therapy in clinical trials.

Methylation changes induced by a glycodendropeptide immunotherapy and associated to tolerance in mice

“…In addition, the presence of epigenetic changes in promoter regions of several key genes in the development of tolerance and allergic responses may give rise to a gene expression signature that could be used as a predictor of tolerance responses, as seen in a previous allergen sensitized asthma mouse model ( 18 ). Finally, the present study could help in the search of which are the key genes specific of DCs involved in the tolerance development or in the transitory desensitization, supporting previous works performed in gene expression ( 19 ).…”

Indoleamine 2,3-dioxygenase 1 activation in mature cDC1 promotes tolerogenic education of inflammatory cDC2 via metabolic communication

“…Dendritic cells (DCs) play a vital role in innate and adaptive host immunity, efficiently priming naive lymphocytes ( Bošnjak et al., 2022 ; Steinman and Hemmi, 2006 ). However, DCs are also important in maintaining immune homeostasis and self-tolerance ( Pulendran et al., 2000 ; Robertson et al., 2021 ; Steinman et al., 2003 ). The type of DC as well as the extent of maturation or activation can profoundly affect their capability to induce immunity or tolerance ( Merad et al., 2013 ).…”

Engineered Flt3L Drives Tolerogenic State to Attenuate Anti-drug Antibody Responses

“…Other groups have described tolerogenic mechanisms by which DCs are able to promote tolerance and Treg formation through the production of IL-10, indoleamine 2,3-dioxygenase (IDO), TGF-β, and retinoic acid, as well as protocols to generate such tolerogenic DCs as a therapeutic. (54–60)…”