Comparative transcriptomic profile of tolerogenic dendritic cells differentiated with vitamin D3, dexamethasone and rapamycin

Abstract

Tolerogenic dendritic cell (tolDC)-based therapies have become a promising approach for the treatment of autoimmune diseases by their potential ability to restore immune tolerance in an antigen-specific manner. However, the broad variety of protocols used to generate tolDC in vitro and their functional and phenotypical heterogeneity are evidencing the need to find robust biomarkers as a key point towards their translation into the clinic, as well as better understanding the mechanisms involved in the induction of immune tolerance. With that aim, in this study we have compared the transcriptomic profile of tolDC induced with either vitamin D3 (vitD3-tolDC), dexamethasone (dexa-tolDC) or rapamycin (rapa-tolDC) through a microarray analysis in 5 healthy donors. The results evidenced that common differentially expressed genes could not be found for the three different tolDC protocols. However, individually, CYP24A1, MUCL1 and MAP7 for vitD3-tolDC; CD163, CCL18, C1QB and C1QC for dexa-tolDC; and CNGA1 and CYP7B1 for rapa-tolDC, constituted good candidate biomarkers for each respective cellular product. In addition, a further gene set enrichment analysis of the data revealed that dexa-tolDC and vitD3-tolDC share several immune regulatory and anti-inflammatory pathways, while rapa-tolDC seem to be playing a totally different role towards tolerance induction through a strong immunosuppression of their cellular processes.

Tolerogenic Dendritic Cells: The Pearl of Immunotherapy in Organ Transplantation

“…Transcriptome and proteome studies illustrate distinctive molecular signatures of Tol-DC. Though it is still difficult to find uniform surface markers to define Tol-DC, it is reported that some genes, such as CYP24A1, MUCL1, MAP7, CCL18, C1QB, C1QC, CYP7B1, and CNGA1, could be considered as possible biomarkers for Tol-DC ( 23 ).…”

“…VitD3-Tol-DC show low expression of MHC-II, CD80, CD86, and CD40 and high secretion or expression of IL-10, indoleamine-2,3-dioxygenase (IDO), and even immunoglobulin-like transcript 3 (ILT3) ( 35 – 38 ). Several inflammatory pathways are involved in this process, such as extracellular signal-regulated kinase (ERK) 1/2 signaling cascade and specificity protein 1 (SP1) signaling factor and nuclear factor-kappa B (NF-κB) ( 23 ). A recent study indicates that high expressions of both MAP7 and MUCL1 genes are observed in VitD3-Tol-DC ( 39 ).…”

Engineering Biomaterials to Direct Innate Immunity

“…Many of these agonists exploit the potent inflammatory response mounted by TLR signaling. [112] A study from Gammon et al extended this mechanistic data by integration of rapamycin into biodegradable MPs for the control of T cell phenotypes. Madan-Lala utilized a PLGA MP as a platform for testing the innate immune response to different combinations of clinically relevant TLR agonists including: Pam3CSK4 (TLR2 agonist), MPLA (TLR4 agonist), R837 (TLR7 agonist), and CpG (TLR9 agonist).…”

“…Interestingly, tissue-resident macrophages engulfed a higher percentage of negatively charged NPs. Reproduced according to the terms of the Creative Commons Attribution 4.0 International License, [112] Copyright 2018, Springer Nature. Comparisons between polystyrene and PLGA have demonstrated recruitment of different cell types and differential activation of inflammasomes, which operate through the NOD-like receptor pathway to trigger innate activation.…”

Comparison of dendritic cells obtained from autoimmunty-prone and resistant rats

“…CYP24A1, MUCL1 and MAP7 were identified as genes whose expression is differentially expressed in human vitamin D3-induced tolDC versus both mDC and immature DC (iDC). Additionally, ATP6VOD2, CAMP and SPARC were identified as differentially expressed genes in vitamin D3induced tolDC in comparison to mDC [19]. Therefore, an analysis of the expression of these six genes was performed in rat DC ( Fig 5).…”