Unique glandular ex-vivo Th1 and Th17 receptor motifs in Sjögren's syndrome patients using single-cell analysis

Voigt, Alexandria; Bohn, Katherine; Sukumaran, Sukesh; Stewart, Carol M.; Bhattacharya, Indraneel; Nguyen, Cuong Q.

doi:10.1016/j.clim.2018.04.009

Cited by 26 publications

(17 citation statements)

References 55 publications

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“…Suggestive GSEA results that did not pass correction for multiple comparison testing showed trends toward a dearth of Th17 cells and enrichment of Tcm and activated Treg populations in SS SG biopsies. The lack of detection of a Th17 gene signature among salivary gland CD4 + T cells is consistent with a prior report finding that CD4 + T cells with IL-17 production potential occur at low frequency (<0.2%) among CD4 + T cells in SS SG tissue [46]. Our study, which sampled 200 sorted memory CD4 + T cells per subject, was designed to detect prevalent differentiation states and to ensure adequate sampling from the non-SS control group.…”

Section: Discussionsupporting

confidence: 86%

Sjögren’s Syndrome Minor Salivary Gland CD4+ Memory T Cells Associate with Glandular Disease Features and Have a Germinal Center T Follicular Helper Transcriptional Profile

Joachims

Leehan

Dozmorov

et al. 2020

JCM

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To assess the types of salivary gland (SG) T cells contributing to Sjögren’s syndrome (SS), we evaluated SG T cell subtypes for association with disease features and compared the SG CD4+ memory T cell transcriptomes of subjects with either primary SS (pSS) or non-SS sicca (nSS). SG biopsies were evaluated for proportions and absolute numbers of CD4+ and CD8+ T cells. SG memory CD4+ T cells were evaluated for gene expression by microarray. Differentially-expressed genes were identified, and gene set enrichment and pathways analyses were performed. CD4+CD45RA− T cells were increased in pSS compared to nSS subjects (33.2% vs. 22.2%, p < 0.0001), while CD8+CD45RA− T cells were decreased (38.5% vs. 46.0%, p = 0.0014). SG fibrosis positively correlated with numbers of memory T cells. Proportions of SG CD4+CD45RA− T cells correlated with focus score (r = 0.43, p < 0.0001), corneal damage (r = 0.43, p < 0.0001), and serum Ro antibodies (r = 0.40, p < 0.0001). Differentially-expressed genes in CD4+CD45RA− cells indicated a T follicular helper (Tfh) profile, increased homing and increased cellular interactions. Predicted upstream drivers of the Tfh signature included TCR, TNF, TGF-β1, IL-4, and IL-21. In conclusion, the proportions and numbers of SG memory CD4+ T cells associate with key SS features, consistent with a central role in disease pathogenesis.

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Section: Discussionsupporting

confidence: 86%

Sjögren’s Syndrome Minor Salivary Gland CD4+ Memory T Cells Associate with Glandular Disease Features and Have a Germinal Center T Follicular Helper Transcriptional Profile

Joachims

Leehan

Dozmorov

et al. 2020

JCM

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“…reported that the TRBV3-1 gene was highly expressed in Th1 and Th17 cells of primary Sjögren's syndrome patients 48 . Further, the abnormal expression of TRBV3-1 and TRBJ2-7 might be associated with the pathogenesis of immune-related diseases.…”

Section: Discussionmentioning

confidence: 99%

TCR repertoire analysis reveals effector memory T cells differentiation into Th17 cells in rheumatoid arthritis

Jiang

Wang

Zhou

et al. 2019

Preprint

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contributed equally to this work. Abstract: The pathogenesis of rheumatoid arthritis (RA), a systemic autoimmune disease characterized by autoreactive T-cell accumulation and pro-inflammatory cytokine overproduction, is unclear. Systematically addressing T-cell receptor (TCR) repertoires of different CD4+ T-cell subsets could help understand RA pathogenesis.Here, peripheral CD4+ T cells from treatment-naïve RA patients and healthy controls were sorted into seven subsets including naïve, effector, central memory, effector memory (EMT), Th1, Th17, and regulatory T cells. T-cell receptor β chain repertoires were then analyzed by next-generation sequencing. We identified T-cell clonal expansion in EMT and Th17 cells, with highly similar TCR repertoires between them.Ex vivo experiments demonstrated the preferred differentiation from EMT to Th17 cells in RA. Moreover, TCR diversity in subsets including Th17 was negatively

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“…Th1 and Th17 cells have long been implicated as crucial mediators at early stages of SS pathology, contributing in shape up the inflammatory microenvironment ( Figure 1 ). Such notion was emphasized by the fact that both pSS-infiltrating activated Th1 and Th17 subsets presented restricted clonal diversities with TCR recognizing common autoantigen unique to pSS [ 27 ]. Th1 cells have also been narrowly associated to development and disease severity, owing to their selective infiltration into target tissues, analyzed by the presence of the transcription factor T-bet and IFN-γ [ 28 ].…”

Section: Th1/th17 Cells: Primordial Effectors Coordinating the Infmentioning

confidence: 99%

T Cells Subsets in the Immunopathology and Treatment of Sjogren’s Syndrome

2020

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Sjogren’s syndrome (SS) is an autoimmune disease whose pathogenesis is characterized by an exacerbated T cell infiltration in exocrine glands, markedly associated to the inflammatory and detrimental features as well as the disease progression. Several helper T cell subsets sequentially converge at different stages of the ailment, becoming involved in specific pathologic roles. Initially, their activated phenotype endows them with high migratory properties and increased pro-inflammatory cytokine secretion in target tissues. Later, the accumulation of immunomodulatory T cells-derived factors, such as IL-17, IFN-γ, or IL-21, preserve the inflammatory environment. These effects favor strong B cell activation, instigating an extrafollicular antibody response in ectopic lymphoid structures mediated by T follicular helper cells (Tfh) and leading to disease progression. Additionally, the memory effector phenotype of CD8+ T cells present in SS patients suggests that the presence of auto-antigen restricted CD8+ T cells might trigger time-dependent and specific immune responses. Regarding the protective roles of traditional regulatory T cells (Treg), uncertain evidence shows decrease or invariable numbers of circulating and infiltrating cells. Nevertheless, an emerging Treg subset named follicular regulatory T cells (Tfr) seems to play a critical protective role owing to their deficiency that enhances SS development. In this review, the authors summarize the current knowledge of T cells subsets contribution to the SS immunopathology, focusing on the cellular and biomolecular properties allowing them to infiltrate and to harm target tissues, and that simultaneously make them key therapeutic targets for SS treatment.

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Unique glandular ex-vivo Th1 and Th17 receptor motifs in Sjögren's syndrome patients using single-cell analysis

Cited by 26 publications

References 55 publications

Sjögren’s Syndrome Minor Salivary Gland CD4+ Memory T Cells Associate with Glandular Disease Features and Have a Germinal Center T Follicular Helper Transcriptional Profile

Sjögren’s Syndrome Minor Salivary Gland CD4+ Memory T Cells Associate with Glandular Disease Features and Have a Germinal Center T Follicular Helper Transcriptional Profile

TCR repertoire analysis reveals effector memory T cells differentiation into Th17 cells in rheumatoid arthritis

T Cells Subsets in the Immunopathology and Treatment of Sjogren’s Syndrome

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