Longitudinal analysis of T-cell receptor repertoires reveals persistence of antigen-driven CD4+ and CD8+ T-cell clusters in systemic sclerosis

Servaas, Nila Hendrika; Zaaraoui-Boutahar, Fatiha; Wichers, Catharina G K; Ottria, Andrea; Chouri, Eleni; Affandi, Alsya J.; Silva-Cardoso, Sandra; Kroef, Maarten van der; Carvalheiro, Tiago; Wijk, Femke van; Andeweg, Arno C.; Pandit, Aridaman

doi:10.1016/j.jaut.2020.102574

Cited by 23 publications

(20 citation statements)

References 62 publications

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“…Compared with HC, the proportion of circulating CD8 + T cells in SSc patients in the early stage was decreased and related to the prolonged course of disease (Fox et al, 2021). Although according to a 2021 study, antigen-driven expansion of CD8 + T cells had a high temporal persistence in the blood of SSc patients (Servaas et al, 2021). In addition, the CD8 + T cells lacking CD28 expression in the peripheral blood in SSc and skin lesions have been detected.…”

Section: Cd8 + Ctl Cellsmentioning

confidence: 99%

Contributions of Immune Cells and Stromal Cells to the Pathogenesis of Systemic Sclerosis: Recent Insights

et al. 2022

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Systemic sclerosis (SSc) is a multisystem rheumatic disease characterized by vascular dysfunction, autoimmune abnormalities, and progressive organ fibrosis. A series of studies in SSc patients and fibrotic models suggest that immune cells, fibroblasts, and endothelial cells participate in inflammation and aberrant tissue repair. Furthermore, the growing number of studies on single-cell RNA sequencing (scRNA-seq) technology in SSc elaborate on the transcriptomics and heterogeneities of these cell subsets significantly. In this review, we summarize the current knowledge regarding immune cells and stromal cells in SSc patients and discuss their potential roles in SSc pathogenesis, focusing on recent advances in the new subtypes by scRNA-seq.

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Section: Cd8 + Ctl Cellsmentioning

confidence: 99%

Contributions of Immune Cells and Stromal Cells to the Pathogenesis of Systemic Sclerosis: Recent Insights

et al. 2022

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“…Vettori et al investigate the dynamics and the function of T cell-fibroblast interaction in SSc, using an experimental co-culture setting, highlighting the role of IL-17A. IL-17 has been proposed to have a central role in SSc (9). The authors show that T cellfibroblast co-cultures overexpress IL17A and IL17RA, cocultured fibroblasts also upregulate IL-17A targets while two key effectors of the TGF-b signaling, TGFBR2 and SMAD3, are downregulated.…”

Section: Editorial On the Research Topicmentioning

confidence: 99%

Editorial: Etiopathogenesis of Systemic Sclerosis: An Update

Stifano

Palma

2021

Front. Immunol.

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“…Since cDC2s are indispensable for CD4+ T-cell activation, and CD4+ T-cells contribute to SSc pathogenesis [16]- [19], we next investigated the role of NR4As in priming cDC2s for autologous CD4+ T-cell activation (Figure 6A, Supplementary figure 4). cDC2s pretreated with NR4A agonists C-DIM5 and C-DIM12 were less capable of inducing IFNγ production by CD4+ T-cells compared to control (Figure 6B).…”

Section: Nr4a Activation Can Decrease the Cd4+ T-cell Stimulatory Capacity Of Cdc2smentioning

confidence: 99%

“…Furthermore, cDCs are a rather heterogeneous population, with CD1c+ cDCs (cDC2s) having a high capacity for priming CD4+ T cells [15]. Given the well-established pathogenic role of T cells in SSc [16]- [19], cDC2s are a highly interesting subset to investigate in the disease.…”

Section: Introductionmentioning

confidence: 99%

Nuclear receptor subfamily 4A signaling as a key disease pathway of CD1c+ dendritic cell dysregulation in systemic sclerosis

Servaas

Hiddingh

Chouri

et al. 2021

Preprint

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ObjectivesTo identify key disease pathways driving conventional dendritic cell (cDC) alterations in Systemic Sclerosis (SSc).MethodsTranscriptomic profiling was performed on peripheral blood CD1c+ cDCs (cDC2s) isolated from 12 healthy donors and 48 SSc patients with all major disease subtypes. Differential expression analysis comparing the different SSc subtypes and healthy donors was performed to uncover genes dysregulated in SSc. To identify biologically relevant pathways, a gene co-expression network was built using Weighted Gene Correlation Network Analysis. We validated the role of key transcriptional regulators using ChIP-sequencing and in vitro functional assays.ResultsWe identified 17 modules of co-expressed genes in cDC2s that correlated with SSc subtypes and key clinical traits including auto-antibodies, skin score, and occurrence of interstitial lung disease. A module of immune regulatory genes was markedly down regulated in patients with the diffuse SSc subtype characterized by severe fibrosis. Transcriptional regulatory network analysis performed on this module predicted NR4A (nuclear receptor 4A) subfamily (NR4A1, NR4A2, NR4A3) genes as the key transcriptional mediators of inflammation. Indeed, ChIP-sequencing analysis supported that these NR4A members target numerous differentially expressed genes in SSc cDC2s. Inclusion of NR4A receptor agonists in culture-based experiments provided functional proof that dysregulation of NR4As affects cytokine production by cDC2s and modulates downstream T-cell activation.ConclusionsNR4A1, NR4A2 and NR4A3 are important regulators of immunosuppressive and fibrosis-associated pathways in SSc cDC2s. Thus, the NR4A family represent novel potential targets to restore cDC homeostasis in SSc.KEY MESSAGESWhat is already known about this subject?CD1c+ conventional dendritic cells (cDC2s) are implicated as key players in Systemic Sclerosis (SSc), but key molecular mechanisms underlying their dysregulation were unknown.What does this study add?Transcriptomic analysis and network analysis identified modules of coexpressed genes in cDC2s that correlated with SSc subtypes and key clinical traits.The NR4A (nuclear receptor 4A) subfamily (NR4A1, NR4A2, NR4A3) genes act as master regulators of key immune regulatory genes dysregulated in SSc cDC2s, as shown by multi-omics integration analysis using transcriptomics and targeted ChIP-sequencing.Pharmacological activation of NR4As inhibits pro-inflammatory cytokine production and CD4+ T-cell activation by cDC2s.How might this impact on clinical practice or future developments?NR4As are attractive candidates for novel treatment options to attenuate pro-inflammatory and pro-fibrotic responses in SSc patients.

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Longitudinal analysis of T-cell receptor repertoires reveals persistence of antigen-driven CD4+ and CD8+ T-cell clusters in systemic sclerosis

Cited by 23 publications

References 62 publications

Contributions of Immune Cells and Stromal Cells to the Pathogenesis of Systemic Sclerosis: Recent Insights

Contributions of Immune Cells and Stromal Cells to the Pathogenesis of Systemic Sclerosis: Recent Insights

Editorial: Etiopathogenesis of Systemic Sclerosis: An Update

Nuclear receptor subfamily 4A signaling as a key disease pathway of CD1c+ dendritic cell dysregulation in systemic sclerosis

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