The impact of biological therapy on regulatory T cells in rheumatoid arthritis

Byng-Maddick, Rachel; Ehrenstein, Michael R.

doi:10.1093/rheumatology/keu487

Cited by 67 publications

(47 citation statements)

References 85 publications

(85 reference statements)

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“…Microbe-derived metabolites can drive T reg cells to maintain homeostasis and tolerance, but physical contact and TLR ligation that indicate invading pathogenic bacteria instead allow proliferation and inflammatory function. Similarly, T reg cells often accumulate in but fail to suppress inflammation in chronic autoimmune diseases, such as systemic lupus erythematosus and rheumatoid arthritis 44,45 . Conversely, these pathways might promote the suppressive function of T reg cells in tumors, in which glycolysis might be limited by reduced glucose or elevated lactate concentrations.…”

Section: Discussionmentioning

confidence: 99%

Foxp3 and Toll-like receptor signaling balance Treg cell anabolic metabolism for suppression

et al. 2016

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CD4+ effector T cells (Teff cells) and regulatory T cells (Treg cells) undergo metabolic reprogramming to support proliferation and immunological function. Although signaling via the lipid kinase PI(3)K (phosphatidylinositol-3-OH kinase), the serine-threonine kinase Akt and the metabolic checkpoint kinase complex mTORC1 induces both expression of the glucose transporter Glut1 and aerobic glycolysis for Teff cell proliferation and inflammatory function, the mechanisms that regulate Treg cell metabolism and function remain unclear. We found that Toll-like receptor (TLR) signals that promote Treg cell proliferation increased PI(3)K-Akt-mTORC1 signaling, glycolysis and expression of Glut1. However, TLR-induced mTORC1 signaling also impaired Treg cell suppressive capacity. Conversely, the transcription factor Foxp3 opposed PI(3)K-Akt-mTORC1 signaling to diminish glycolysis and anabolic metabolism while increasing oxidative and catabolic metabolism. Notably, Glut1 expression was sufficient to increase the number of Treg cells, but it reduced their suppressive capacity and Foxp3 expression. Thus, inflammatory signals and Foxp3 balance mTORC1 signaling and glucose metabolism to control the proliferation and suppressive function of Treg cells.

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Section: Discussionmentioning

confidence: 99%

Foxp3 and Toll-like receptor signaling balance Treg cell anabolic metabolism for suppression

et al. 2016

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“…Among several possible mechanisms, one is suppression of B-cell functions. Autoreactive B cells not only produce autoantibody that can potentiate immune responses but also can directly interact with T cells by antigen presentation, leading to cytokine production and germinal center formation [1, 35]. A pathogenic role for B cells other than antibody production was confirmed by the efficacy of rituximab with limited reduction of ACPA titers in RA [36].…”

Section: Discussionmentioning

confidence: 99%

Interleukin-10-producing LAG3+ regulatory T cells are associated with disease activity and abatacept treatment in rheumatoid arthritis

et al. 2017

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BackgroundRegulatory T cells (Tregs) play a role in the suppression of inflammation in autoimmune diseases, and lymphocyte activation gene 3 (LAG3) was reported as a marker of interleukin (IL)-10-producing Tregs. We aimed to clarify the function of human IL-10-producing CD4+CD25−LAG3+ T cells (LAG3+ Tregs) and their association with rheumatoid arthritis (RA).MethodsLAG3+ Tregs of human peripheral blood mononuclear cells (PBMCs) were cultured with B cells and follicular helper T cells to examine antibody suppression effects. The frequency of LAG3+ Tregs was evaluated in peripheral blood samples from 101 healthy donors and 85 patients with RA. In patients treated with abatacept, PBMC samples were analyzed before and after treatment. Naive CD4+ T cells were sorted and cultured in the presence of abatacept, followed by flow cytometric analysis and function assays.ResultsLAG3+ Tregs produced high amounts of IL-10 and interferon-γ, and they suppressed B-cell antibody production more strongly than CD25+ Tregs. Cell-to-cell contact was required for the suppressive function of LAG3+ Tregs. The frequency of LAG3+ Tregs was lower in patients with RA, especially those with higher Clinical Disease Activity Index scores. LAG3+ Tregs significantly increased after 6 months of abatacept treatment, whereas CD25+ Tregs generally decreased. Abatacept treatment in vitro conferred LAG3 and EGR2 expression on naive CD4+ T cells, and abatacept-treated CD4+ T cells exhibited suppressive activity.ConclusionsIL-10-producing LAG3+ Tregs are associated with the immunopathology and therapeutic response in RA. LAG3+ Tregs may participate in a mechanism for the anti-inflammatory and immune-modulating effects of targeted therapy for costimulation.Electronic supplementary materialThe online version of this article (doi:10.1186/s13075-017-1309-x) contains supplementary material, which is available to authorized users.

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“…Activation of PKB/c-Akt positively regulates the production of proinflammatory cytokines, including TNF, and TNF itself can also induce PKB/c-Akt activation. Blocking this positive feedback loop through anti-TNF therapy might thus also result in the sensitization of T effs to suppression [14,21,22].…”

Section: Discussionmentioning

confidence: 99%

“…Treatment with anti-TNF agents restored the suppressive capacity of T regs and gave rise to a newly differentiated T reg population in RA patients [9]. Although it is known that TNF exerts its effect on T regs by binding to TNF-receptor 2 (TNFR2), which is expressed highly on T regs , it remains unclear whether TNF-TNFR2 interaction potentiates or down-modulates T reg function [10][11][12][13][14].…”

Section: Introductionmentioning

confidence: 99%

Infliximab therapy balances regulatory T cells, tumour necrosis factor receptor 2 (TNFR2) expression and soluble TNFR2 in sarcoidosis

Verwoerd¹,

Hijdra²,

Vorselaars³

et al. 2016

Clinical and Experimental Immunology

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SummarySarcoidosis is a systemic granulomatous disease of unknown aetiology that most commonly affects the lungs. Although elevated levels of regulatory T cells (T regs ) have been reported, the extent to which they play a role in sarcoidosis pathogenesis remains unclear. Tumour necrosis factor (TNF) is thought to be one of the driving forces behind granuloma formation, illustrated by the efficacy of infliximab in severe sarcoidosis. T regs express TNF receptor 2 (TNFR2) highly. Here, we examined the influence of infliximab therapy on T regs and (soluble) TNFR2 levels in sarcoidosis, and correlated these with response to therapy. We observed that relative frequencies of T regs were significantly higher in patients (n 5 54) compared to healthy controls (n 5 26; median 6Á73 versus 4Á36%; P < 0Á001) and decreased following therapy (4Á95; P < 0Á001). Baseline TNFR2 expression on T regs was increased significantly in patients versus controls (99Á4 versus 96Á2%; P 5 0Á031), and also in responders to therapy versus non-responders (99Á6 versus 97Á3%; P 5 0Á012). Furthermore, baseline soluble TNFR2 (sTNFR2) was higher in responders than in non-responders (mean 174 versus 107 pg/ml; P 5 0Á015). After treatment, responders showed a significant reduction in sTNFR2 levels in peripheral blood (244Á7 pg/ml; P < 0Á001), in contrast to non-responders (13Á59 pg/ml). Our results demonstrated that T reg frequencies and TNFR2 expression on T regs are increased in sarcoidosis, followed by a decline during infliximab therapy, suggesting a pathophysiological role of this T cell subset. Interestingly, sTNFR2 levels at baseline differed significantly between responders and non-responders, making it a potential marker in predicting which patients might benefit from infliximab.

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The impact of biological therapy on regulatory T cells in rheumatoid arthritis

Cited by 67 publications

References 85 publications

Foxp3 and Toll-like receptor signaling balance Treg cell anabolic metabolism for suppression

Foxp3 and Toll-like receptor signaling balance Treg cell anabolic metabolism for suppression

Interleukin-10-producing LAG3+ regulatory T cells are associated with disease activity and abatacept treatment in rheumatoid arthritis

Infliximab therapy balances regulatory T cells, tumour necrosis factor receptor 2 (TNFR2) expression and soluble TNFR2 in sarcoidosis

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