Treg cells in health and autoimmune diseases: New insights from single cell analysis

Scheinecker, Clemens; Göschl, Lisa; Bonelli, Michael

doi:10.1016/j.jaut.2019.102376

Cited by 130 publications

(96 citation statements)

References 270 publications

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“…In addition, in this new era of gene and cell therapy development, technological advances such as gene therapyinduced by target specificity or methods for delivering one or more genes to treat RA (175), single-cell transcriptome sRNAseq has been used to analyze the expression of hundreds of genes in a single cell (176). The development of ATAC-seq has facilitated analyses of the occupancy of transcription factors in specific cell types (177).…”

Section: Discussionmentioning

confidence: 99%

Function and Role of Regulatory T Cells in Rheumatoid Arthritis

et al. 2021

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Rheumatoid arthritis (RA) is a systemic and heterogeneous autoimmune disease with symmetrical polyarthritis as its critical clinical manifestation. The basic cause of autoimmune diseases is the loss of tolerance to self or harmless antigens. The loss or functional deficiency of key immune cells, regulatory T (Treg) cells, has been confirmed in human autoimmune diseases. The pathogenesis of RA is complex, and the dysfunction of Tregs is one of the proposed mechanisms underlying the breakdown of self-tolerance leading to the progression of RA. Treg cells are a vital component of peripheral immune tolerance, and the transcription factor Foxp3 plays a major immunosuppressive role. Clinical treatment for RA mainly utilizes drugs to alleviate the progression of disease and relieve disease activity, and the ideal treatment strategy should be to re-induce self-tolerance before obvious tissue injury. Treg cells are one of the ideal options. This review will introduce the classification, mechanism of action, and characteristics of Treg cells in RA, which provides insights into clinical RA treatment.

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Section: Discussionmentioning

confidence: 99%

Function and Role of Regulatory T Cells in Rheumatoid Arthritis

et al. 2021

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“…However, using antibody staining, we were able to find a low expression of the protein CSF-1R on resting CD4 + and CD8 + FOXP3 + Tregs and upon stimulation this expression was significantly increased on activated CD4 + and CD8 + FOXP3 + Tregs. Thus it is possible that IL-34 acts directly on Treg polarization as TGFβ and IL-2, or on Treg function, in addition to acting through monocytes (31), and this will need to be further investigated.…”

Section: Discussionmentioning

confidence: 99%

IL-34 Actions on FOXP3+ Tregs and CD14+ Monocytes Control Human Graft Rejection

et al. 2020

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Cytokines are major players regulating immune responses toward inflammatory and tolerogenic results. In organ and bone marrow transplantation, new reagents are needed to inhibit tissue destructive mechanisms and eventually induce immune tolerance without overall immunosuppression. IL-34 is a cytokine with no significant homology with any other cytokine but that acts preferentially through CSF-1R, as CSF-1 does, and through PTPζ and CD138. Although IL-34 and CSF-1 share actions, a detailed analysis of their effects on immune cells needs further research. We previously showed that both CD4 + and CD8 + FOXP3 + Tregs suppress effector T cells through the production of IL-34, but not CSF-1, and that this action was mediated through antigen-presenting cells. We showed here by single-cell RNAseq and cytofluorimetry that different subsets of human monocytes expressed different levels of CSF-1R, CD138, and PTPζ and that both CD4 + and CD8 + FOXP3 + Tregs expressed higher levels of CSF-1R than conventional T cells. The effects of IL-34 differed in the survival of these different subpopulations of monocytes and RNAseq analysis showed several genes differentially expressed between IL-34, CSF-1, M0, M1, and also M2 macrophages. Acute graftvs.-host disease (aGVHD) in immunodeficient NSG mice injected with human PBMCs was decreased when treated with IL-34 in combination with an anti-CD45RC mAb that depleted conventional T cells. When IL-34-differentiated monocytes were used to expand Tregs in vitro, both CD4 + and CD8 + FOXP3 + Tregs were highly enriched and this effect was superior to the one obtained with CSF-1. Human CD8 + Tregs expanded in vitro with IL-34-differentiated allogeneic monocytes suppressed human immune responses in an NSG mouse aGVHD model humanized with hPBMCs. Overall, we showed that IL-34 induced the differentiation of human monocytes with a particular transcriptional profile and these cells favored the development of potent suppressor FOXP3 + Tregs.

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“…T-reg cells could be of major importance in autoimmune diseases, such as RA, by suppressing several immune cells, including CD8+ and CD4+ T-cells, antigen presenting cells (APCs), natural killer (NK) cells, and dendritic cells [32]. Therefore, RA ameliorating T-reg cells and anti-inflammatory cytokine IL-10 demolishing effects of PCSK9 could contribute to modification of anti TNF-α treatments in RA patients.…”

Section: Discussionmentioning

confidence: 99%

Low levels of PCSK9 are associated with remission in patients with rheumatoid arthritis treated with anti-TNF-α: potential underlying mechanisms

et al. 2021

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Background Proprotein convertase subtilisin kexin 9 (PCSK9) targets the LDL-receptor (LDLR) which raises LDL-levels. In addition, PCSK9 has proinflammatory immunological effects. Here, we investigate the role of PCSK9 in relation to the inflammatory activity in patients with rheumatoid arthritis (RA). Methods PCSK9-levels were determined at baseline by ELISA in 160 patients with RA not previously treated with biologics. The patients started anti-TNF-α (adalimumab, infliximab, or etanercept) treatment and were followed-up for 1 year. Disease activity was determined by DAS28. Effects of PCSK9 on cytokine production from macrophages of healthy individuals and synoviocytes from RA patients and inhibition by anti-PCSK9 antibodies were studied in supernatants by ELISA. Results A significantly lower level of PCSK9 at baseline, p = 0.035, was observed in patients who reached remission within 1 year, defined as DAS28 < 2.6, compared to those not in remission. At 12 months of TNF-α antagonist treatment, the mean DAS28 was reduced but was significantly greater in patients with highest quartile PCSK9 (Q4) compared to those at lowest PCSK9 (Q1) in both crude (p = 0.01) and adjusted analysis (p = 0.004). In vitro, PCSK9 induced TNF-alpha and IL-1beta in macrophages and monocyte chemoattractant protein-1 (MCP1) in synoviocytes. These effects were inhibited by anti-PCSK9 antibodies. Conclusions Low levels of PCSK9 at baseline are associated with being DAS28-responder to anti-TNF-α treatment in RA. An underlying cause could be that PCSK9 stimulates the production of proinflammatory cytokines from macrophages and synoviocytes, effects inhibited by anti-PCSK9 antibodies. PCSK9 could thus play an immunological role in RA.

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Treg cells in health and autoimmune diseases: New insights from single cell analysis

Cited by 130 publications

References 270 publications

Function and Role of Regulatory T Cells in Rheumatoid Arthritis

Function and Role of Regulatory T Cells in Rheumatoid Arthritis

IL-34 Actions on FOXP3+ Tregs and CD14+ Monocytes Control Human Graft Rejection

Low levels of PCSK9 are associated with remission in patients with rheumatoid arthritis treated with anti-TNF-α: potential underlying mechanisms

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