Th1-Like Treg Cells Are Increased But Deficient in Function in Rheumatoid Arthritis

Zhang, Rui; Miao, Jinlin; Zhang, Kui; Zhang, Bei; Luo, Xing; Sun, Haoyang; Zheng, Zhaohui; Zhu, Ping

doi:10.3389/fimmu.2022.863753

Cited by 14 publications

(7 citation statements)

References 39 publications

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“…Intriguingly, most genes in this GEP that were depleted in patients with SjD were also reduced in Treg cells of Stim1/2 Foxp3 mice. In addition, we found an increased IFN signature in all Treg cell subsets, which likely results from increased IFN levels in patients with SjD rather than indicating a Th1-like phenotype that had been identified in several human autoimmune diseases, including T1D, MS and RA [78][79][80] , and in a mouse model of SjD 81 . The IFN signature was present in all CD4 + T cell subsets of patients with SjD and not specific to Treg cells, and the Th1 functional GEP we identified in Th1 cells by NMF was not enriched in Treg cells of patients with SjD.…”

Section: Discussionmentioning

confidence: 53%

“…Alterations in Treg cell function have been reported in several autoimmune diseases, such as T1D, MS and RA [78][79][80][81] . To investigate if Treg cells are dysfunctional in patients with SjD, we analyzed scRNA-seq data of PBMC from SjD and non-SjD samples by NMF with the goal to determine GEPs representing Treg function.…”

Section: Diminished Function Of Memory Treg Cells In Patients With Sjdmentioning

confidence: 99%

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Regulatory T cells and IFN-γ-producing Th1 cells play a critical role in the pathogenesis of Sjögren’s Syndrome

Wang,

Li,

McDermott

et al. 2024

Preprint

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Objectives. Sjögren's Disease (SjD) is an autoimmune disorder characterized by progressive dysfunction, inflammation and destruction of salivary and lacrimal glands, and by extraglandular manifestations. Its etiology and pathophysiology remain incompletely understood, though a role for autoreactive B cells has been considered key. Here, we investigated the role of effector and regulatory T cells in the pathogenesis of SjD. Methods. Histological analysis, RNA-sequencing and flow cytometry were conducted on glands, lungs, eyes and lymphoid tissues of mice with regulatory T cell-specific deletion of stromal interaction proteins (STIM) 1 and 2 (Stim1/2Foxp3), which play key roles in calcium signaling and T cell function. The pathogenicity of T cells fromStim1/2Foxp3mice was investigated through adoptively transfer into lymphopenic host mice. Additionally, single-cell transcriptomic analysis was performed on peripheral blood mononuclear cells (PBMCs) of patients with SjD and control subjects. Results.Stim1/2Foxp3mice develop a severe SjD-like disorder including salivary gland (SG) and lacrimal gland (LG) inflammation and dysfunction, autoantibodies and extraglandular symptoms. SG inflammation inStim1/2Foxp3mice is characterized by T and B cell infiltration, and transcriptionally by a Th1 immune response that correlates strongly with the dysregulation observed in patients with SjD. Adoptive transfer of effector T cells fromStim1/2Foxp3mice demonstrates that the SjD-like disease is driven by interferon (IFN)-γ producing autoreactive CD4+T cells independently of B cells and autoantiboodies. scRNA-seq analysis identifies increased Th1 responses and attenuated memory Treg function in PBMCs of patients with SjD. Conclusions. We report a more accurate mouse model of SjD while providing evidence for a critical role of Treg cells and IFN-γ producing Th1 cells in the pathogenesis of SjD, which may be effective targets for therapy.

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Section: Discussionmentioning

confidence: 53%

Section: Diminished Function Of Memory Treg Cells In Patients With Sjdmentioning

confidence: 99%

Regulatory T cells and IFN-γ-producing Th1 cells play a critical role in the pathogenesis of Sjögren’s Syndrome

Wang,

Li,

McDermott

et al. 2024

Preprint

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“…On the other hand, CD8 + T and CD4 + CD8 + T cells from the OB group showed a different polarization tendency, with preferential Tc1-and T1-like polarization, respectively. Noteworthy, the Tc1 cells from individuals with obesity showed higher expression of CCR5, allowing these cells to migrate into inflammatory sites [38].…”

Section: Discussionmentioning

confidence: 99%

Bariatric Surgery Induces Alterations in the Immune Profile of Peripheral Blood T Cells

Barbosa,

Pinho,

Lázaro

et al. 2024

Biomolecules

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Low-grade inflammation is closely linked to obesity and obesity-related comorbidities; therefore, immune cells have become an important topic in obesity research. Here, we performed a deep phenotypic characterization of circulating T cells in people with obesity, using flow cytometry. Forty-one individuals with obesity (OB) and clinical criteria for bariatric surgery were enrolled in this study. We identified and quantified 44 different circulating T cell subsets and assessed their activation status and the expression of immune-checkpoint molecules, immediately before (T1) and 7–18 months after (T2) the bariatric surgery. Twelve age- and sex-matched healthy individuals (nOB) were also recruited. The OB participants showed higher leukocyte counts and a higher percentage of neutrophils. The percentage of circulating Th1 cells were negatively correlated to HbA1c and insulin levels. OB Th1 cells displayed a higher activation status and lower PD-1 expression. The percentage of Th17 and Th1/17 cells were increased in OB, whereas the CD4+ Tregs’ percentage was decreased. Interestingly, a higher proportion of OB CD4+ Tregs were polarized toward Th1- and Th1/17-like cells and expressed higher levels of CCR5. Bariatric surgery induced the recovery of CD4+ Treg cell levels and the expansion and activation of Tfh and B cells. Our results show alterations in the distribution and phenotype of circulating T cells from OB people, including activation markers and immune-checkpoint proteins, demonstrating that different metabolic profiles are associated to distinct immune profiles, and both are modulated by bariatric surgery.

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“…Under certain inflammatory settings, T reg cells can develop into Th1-like, Th2-like, Th17-like, or Tfh-like T reg cells ( 68 – 72 ) ( Figure 2 ). Th1-like T reg cells acquire a Th1-like phenotype and express the pro-inflammatory cytokine IFN-γ while they lose their suppressive capacity ( 49 , 75 ). Similar, Th2-like and Th17-like T reg cells express the transcription factors GATA-3 or RORγt and secrete IL-13 or IL-17 ( 71 , 76 ).…”

Section: Regulatory T Cellsmentioning

confidence: 99%

“…Interestingly, Th17-like T reg cells have been observed in humans under physiological conditions ( 71 ). In RA, the frequency of Th1-like Treg cells is increased but deficient in function ( 75 ).…”

Section: Regulatory T Cellsmentioning

confidence: 99%

Migration and homeostasis of regulatory T cells in rheumatoid arthritis

2022

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Regulatory T (Treg) cells are garnering increased attention in research related to autoimmune diseases, including rheumatoid arthritis (RA). They play an essential role in the maintenance of immune homeostasis by restricting effector T cell activity. Reduced functions and frequencies of Treg cells contribute to the pathogenesis of RA, a common autoimmune disease which leads to systemic inflammation and erosive joint destruction. Treg cells from patients with RA are characterized by impaired functions and by an altered phenotype. They show increased plasticity towards Th17 cells and a reduced suppressive capacity. Besides the suppressive function of Treg cells, their effectiveness is determined by their ability to migrate into inflamed tissues. In the past years, new mechanisms involved in Treg cell migration have been identified. One example of such a mechanism is the phosphorylation of vasodilator-stimulated phosphoprotein (VASP). Efficient migration of Treg cells requires the presence of VASP. IL-6, a cytokine which is abundantly present in the peripheral blood and in the synovial tissue of RA patients, induces posttranslational modifications of VASP. Recently, it has been shown in mice with collagen-induced arthritis (CIA) that this IL-6 mediated posttranslational modification leads to reduced Treg cell trafficking. Another protein which facilitates Treg cell migration is G-protein-signaling modulator 2 (GPSM2). It modulates G-protein coupled receptor functioning, thereby altering the cellular activity initiated by cell surface receptors in response to extracellular signals. The almost complete lack of GPSM2 in Treg cells from RA patients contributes to their reduced ability to migrate towards inflammatory sites. In this review article, we highlight the newly identified mechanisms of Treg cell migration and review the current knowledge about impaired Treg cell homeostasis in RA.

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Th1-Like Treg Cells Are Increased But Deficient in Function in Rheumatoid Arthritis

Cited by 14 publications

References 39 publications

Regulatory T cells and IFN-γ-producing Th1 cells play a critical role in the pathogenesis of Sjögren’s Syndrome

Regulatory T cells and IFN-γ-producing Th1 cells play a critical role in the pathogenesis of Sjögren’s Syndrome

Bariatric Surgery Induces Alterations in the Immune Profile of Peripheral Blood T Cells

Migration and homeostasis of regulatory T cells in rheumatoid arthritis

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