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Reduction of TLR7/8-Induced IFN-I Responses by Plasmacytoid Dendritic Cells in a Longitudinal Cohort of Trans Men

ABSTRACT: Type I interferons (IFN-I) are important mediators of antiviral immunity and autoimmune diseases. Plasmacytoid dendritic cells (pDCs) from females exert an elevated capacity to produce IFN-I in response to activation of toll-like receptor 7 (TLR7) compared to male pDCs, and both hormones and genes encoded by the X chromosome have been implicated in these sex-specific differences. Using longitudinal samples collected from a cohort of trans men receiving testosterone injections as gender-affirming hormone therapy (GAHT), the impact of testosterone on TLR7-mediated IFN-I production by pDCs was assessed. GAHT induced testosterone and estradiol levels within male reference ranges and increased hemoglobin and hematocrit levels, demonstrating biological activity of testosterone. scRNA seq of pDCs showed downregulation of IFN-I-related gene expression signatures, but also revealed inter-donor heterogeneity on the transcriptional level. Longitudinal quantification of IFN-I protein production by pDCs following TLR7-stimulation showed significant and continuous reduction of IFN-I production in trans men, and reduced expression of IFN-I-stimulated genes. These longitudinal studies in trans men demonstrate that testosterone can reduce IFN-I production by pDCs, and provide novel insights into the immune-modulatory role of testosterone in sex differential IFN-I-mediated immune responses.

ORGANISM(S): Homo sapiens

PROVIDER: GSE231370 | GEO | 2023/11/09

REPOSITORIES: GEO

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2014-07-30 | E-GEOD-57324 | biostudies-arrayexpress

Gene expression analysis in the spleen of wild type, Sle1.3 (lupus mice) and Sle1.3 mice haplodeficient for E2-2 (exhibiting non functional pDCs)

2014-07-30 | GSE57324 | GEO

Single-cell analysis reveals stochastic regulation of type I IFN production by plasmacytoid dendritic cells and identifies host-derived environmental cues as amplifier of type I IFN production

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Project description:Objective: Patients with Systemic Lupus Erythematosus (SLE) have an ongoing interferon (IFN) production due to an activation of plasmacytoid dendritic cells (pDCs), which can be triggered to type I IFN synthesis by RNA containing immune complexes (RNA-IC). Considering emerging data suggesting a role of type III interferon (IFN) in the SLE disease process, we asked if RNA-IC can induce type III IFN production in pDC, and how this production can be regulated. Methods: Peripheral blood mononuclear cells (PBMCs) or immune cell subsets were isolated from healthy blood donors or SLE patients and stimulated with IC containing U1 snRNP and SLE-IgG (RNA-IC). Hydroxychloroquine (HCQ) and an interleukin receptor 1 associated kinase 4 inhibitor (IRAK4i) were added to cell cultures. Cytokine mRNA levels were determined with a microarray and protein levels with immunoassays. Single-cell RNA-sequencing of pDCs using ddSEQ technology was performed. Results: Type III IFN mRNA and protein was induced in RNA-IC stimulated pDC-NK and pDC-B cell co-cultures. A subset of activated pDCs (3%) expressed both type III and type I IFN mRNA. IFN-λ2, IFN-α2b, interleukin (IL)-3, IL-6 or granulocyte-macrophage colony stimulating factor (GM-CSF) enhanced IFN-λ1/3 production 2-5-fold. HCQ and an IRAK4i blocked the RNA-IC-triggered IFN-λ1/3 production (p<0.01). IFN-α2b and GM-CSF increased the proportion of SLE patients producing IFN-λ1/3 in response to RNA-IC from 11 to 33%. Conclusions: Type III IFN production is triggered by RNA-IC in pDCs in a TLR-MyD88-dependent manner, enhanced by NK and B cells as well as several pro-inflammatory cytokines. These results support a contributing role for both type I and type III IFNs in SLE, which needs to be considered when targeting the IFN system in this disease.

2020-05-23 | GSE149415 | GEO

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