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TNF-α sculpts a maturation process in vivo by pruning tolerogenic dendritic cells.

ABSTRACT: It remains unclear how the pro-immunogenic maturation of conventional dendritic cells (cDCs) abrogates their tolerogenic functions. Here, we report that the loss of tolerogenic functions depends on the rapid death of BTLA^hi cDC1s, which, in the steady state, are present in systemic peripheral lymphoid organs and promote tolerance that limits subsequent immune responses. A canonical inducer of maturation, lipopolysaccharide (LPS), initiates a burst of tumor necrosis factor alpha (TNF-α) production and the resultant acute death of BTLA^hi cDC1s mediated by tumor necrosis factor receptor 1. The ablation of these individual tolerogenic cDCs is amplified by TNF-α produced by neighboring cells. This loss of tolerogenic cDCs is transient, accentuating the restoration of homeostatic conditions through biological turnover of cDCs in vivo. Therefore, our results reveal that the abrogation of tolerogenic functions during an acute immunogenic maturation depends on an ablation of the tolerogenic cDC population, resulting in a dynamic remodeling of the cDC functional landscape.

SUBMITTER: Iberg CA

PROVIDER: S-EPMC9113652 | biostudies-literature | 2022 Apr

REPOSITORIES: biostudies-literature

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TNF-α sculpts a maturation process in vivo by pruning tolerogenic dendritic cells.

Iberg Courtney A CA Bourque Jessica J Fallahee Ian I Son Sungho S Hawiger Daniel D

Cell reports 20220401 2

It remains unclear how the pro-immunogenic maturation of conventional dendritic cells (cDCs) abrogates their tolerogenic functions. Here, we report that the loss of tolerogenic functions depends on the rapid death of BTLA<sup>hi</sup> cDC1s, which, in the steady state, are present in systemic peripheral lymphoid organs and promote tolerance that limits subsequent immune responses. A canonical inducer of maturation, lipopolysaccharide (LPS), initiates a burst of tumor necrosis factor alpha (TNF-α ...[more]

PMID: 35417681

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Project description:SP140 is an epigenetic reader protein expressed predominantly in immune cells. GWAS studies have shown an association between SP140 single nucleotide polymorphisms (SNPs) and diverse autoimmune and inflammatory diseases, suggesting a possible pathogenic role for SP140 in immune-mediated diseases. We previously demonstrated that treatment of human macrophages with the novel selective inhibitor of the SP140 protein (GSK761) reduced the expression of endotoxin-induced cytokines, implicating a role of SP140 in the function of inflammatory macrophages. In this study, we investigated the effects of GSK761 on in vitro human dendritic cell (DC) differentiation and maturation, assessing the expression of cytokines and co-stimulatory molecules and their capacity to stimulate T-cell activation and induce phenotypic changes. In DCs, lipopolysaccharide (LPS) stimulation induced an increase in SP140 expression and its recruitment to transcription start sites (TSS) of pro-inflammatory cytokine genes. Moreover, LPS-induced cytokines such as TNF, IL-6, and IL-1β were reduced in GSK761- or SP140 siRNA- treated DCs. Although GSK761 did not significantly affect the expression of surface markers that define the differentiation of CD14+ monocytes into immature DCs (iDCs), subsequent maturation of iDCs to mature DCs was significantly inhibited. GSK761 strongly reduced expression of the maturation marker CD83, the co-stimulatory molecules CD80 and CD86, and the lipid-antigen presentation molecule CD1b. Finally, when the ability of DCs to stimulate recall T-cell responses by vaccine-specific T cells was assessed, T cells stimulated by GSK761-treated DCs showed reduced TBX21 and RORA expression and increased FOXP3 expression, indicating a preferential generation of regulatory T cells. Overall, this study suggests that SP140 inhibition enhances the tolerogenic properties of DCs, supporting the rationale of targeting SP140 in autoimmune and inflammatory diseases where DC-mediated inflammatory responses contribute to disease pathogenesis.

Dataset Information

TNF-α sculpts a maturation process in vivo by pruning tolerogenic dendritic cells.

Publications

TNF-α sculpts a maturation process in vivo by pruning tolerogenic dendritic cells.

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