TLR2 Stimulation Regulates the Balance between Regulatory T Cell and Th17 Function: A Novel Mechanism of Reduced Regulatory T Cell Function in Multiple Sclerosis

Nyirenda, Mukanthu; Morandi, Elena; Vinkemeier, Uwe; Constantin‐Teodosiu, Dumitru; Drinkwater, Sophie; Mee, Maureen; King, Lloyd; Podda, Giulio; Zhang, Guang‐Xian; Ghaemmaghami, Amir M.; Constantinescu, Cris S.; Bar‐Or, Amit; Gran, Bruno

doi:10.4049/jimmunol.1400472

Cited by 64 publications

(61 citation statements)

References 66 publications

(112 reference statements)

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“…Moreover, reversal of regulatory T cell suppressive function has been reported following TLR-2 co-stimulation (18, 54), and if this occurs in vivo , could promote proinflammatory conditions associated with autoimmunity. It is notable that the precise role of TLR in the development of these disorders remains controversial, however, as both induction of tolerance and exacerbation of autoreactivity have been described.…”

Section: Discussionmentioning

confidence: 99%

Direct TLR-2 Costimulation Unmasks the Proinflammatory Potential of Neonatal CD4+ T Cells

Sinnott

Park

Boer

et al. 2016

The Journal of Immunology

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Neonatal CD4+ T cells have traditionally been viewed as deficient in their capacity to produce Th-1 cytokines in response to polyclonal or antigen specific stimuli. Thus, defining unique aspects of CD4+ T cell activation and development into Th-1 effector cells in neonates is essential to the successful development of novel vaccines and immunotherapies to protect infants from intracellular pathogens. Using highly purified naïve CD4+ T cells derived from cord and adult peripheral blood, we compared the impact of anti-CD3 stimulation plus co-stimulation through TLR-2 performed in the absence of APC, on CD4+ T cell cytokine production, proliferation, and expression of activation markers. In both age groups, TLR-2 co-stimulation elicited activation of naïve CD4+ T cells, characterized by robust production of IL-2 as well as key Th-1 type cytokines IFN-γ and TNF-α. TLR-2 co-stimulation also dramatically reduced naïve T cell production of the immunosuppressive cytokine IL-10. We observed that neonatal naïve CD4+ T cells are uniquely sensitive to TLR-2 mediated co-stimulation, which enabled them to produce equivalent amounts of IFN-γ and more IL-2 when compared to adult responses. Thus, neonatal CD4+ T cells have a distinctive propensity to utilize TLR-2 mediated co-stimulation for development into pro-inflammatory Th-1 effectors, and interventions that target CD4+ T cell TLR-2 mediated responses may be exploited to enhance neonatal adaptive immunity.

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Section: Discussionmentioning

confidence: 99%

Direct TLR-2 Costimulation Unmasks the Proinflammatory Potential of Neonatal CD4+ T Cells

Sinnott

Park

Boer

et al. 2016

The Journal of Immunology

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“…Helminth-infected MS patients were found to have TLR2-dependent programming of dendritic cells that induced regulatory T cells (Tregs), suppressed production of proinflammatory cytokines, and was associated with upregulation of genes involved in retinoic acid biosynthesis and metabolism (4). In contrast, Nyirenda et al (5) reported that TLR2 activation is involved in the reduced Treg function reported in MS. These authors found that stimulation with Pam3CSK, a TLR1/TLR2 agonist, reduced Treg function and induced Th17 skewing, and this effect was enhanced in MS patients compared with healthy controls.…”

mentioning

confidence: 88%

TLR Tolerance as a Treatment for Central Nervous System Autoimmunity

Anstadt

Fujiwara

Wasko

et al. 2016

The Journal of Immunology

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The role of TLR signaling in multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE) is unclear. This role is especially controversial in models of adoptive transfer EAE in which no adjuvant and no TLR ligands are administered. We recently reported that a microbiome-derived TLR2 ligand, Lipid 654 (L654), is present in healthy human serum but significantly decreased in the serum of MS patients. This suggested that microbiome products that gain access to the systemic circulation, rather than being proinflammatory, may normally play an immune-regulatory role by maintaining a state of relative TLR tolerance. Therefore, a loss of microbiome-mediated TLR tolerance, as suggested by lower serum levels of L654, may play a role in the pathogenesis of MS. As proof of concept we asked whether administering low-level TLR2 ligands in adoptive transfer EAE induces TLR2 tolerance and attenuates disease. We administered low-level Pam2CSK4 or L654 to mice receiving encephalitogenic cells and in doing so induced both TLR2 tolerance and attenuation of EAE. Disease attenuation was accompanied in the CNS by a decrease in macrophage activation, a decrease in a specific proinflammatory macrophage population, and a decrease in Th17 cells. In addition, disease attenuation was associated with an increase in splenic type 1 regulatory T cells. Kinetic tolerance induction studies revealed a critical period for TLR2 involvement in adoptive transfer EAE. Overall, these results suggest that inducing TLR tolerance may offer a new approach to treating CNS autoimmune diseases such as MS.

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“…Wang et al [29] observed that IFN-β stimulates IL-10 production. This cytokine is instrumental in dampening neuroinflammation [7, 12, 27, 30]. It was previously demonstrated that a high production of TLR-induced IL-10 during helminth infections can alter the clinical course of MS [28, 31, 32], indicating the central role of IL-10 in the control of exacerbations and disability scores.…”

Section: Discussionmentioning

confidence: 99%

“…There is evidence that the activation of TLR2 is implicated in triggering the neuronal damage observed in MS as TLR2-mediated signaling may lead to neuroinflammation [26]. Previous studies found that the higher levels of TLR2 expression in patients than in healthy controls promoted the activity and progression of MS [27]. Thus, IFN-β seems to benefit patients who use it regularly as it reduces the responsiveness of TLR2 for TNF-α production or, possibly, because it induces lower expression of this receptor in the cells of the patients [28].…”

Section: Discussionmentioning

confidence: 99%

Interferon-Beta Treatment Differentially Alters TLR2 and TLR4-Dependent Cytokine Production in Multiple Sclerosis Patients

Oliveira

Gomes

Gomides

et al. 2019

Neuroimmunomodulation

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Objective: Multiple sclerosis (MS) is a multifactorial chronic disease that affects the central nervous system (CNS). Toll-like receptors (TLRs) play a central role in cytokine production after pathogen- and danger-associated molecular patterns (PAMPs and DAMPs) and contribute to CNS damage in MS patients. Here, we evaluated the effects of interferon (IFN)-β treatment in TLR2 and TLR4-dependent cytokine production and mRNA expression in whole-blood cell cultures from MS patients. Methods: We evaluated cytokine production by ELISA from whole-blood cell culture supernatants and mRNA expression by real-time polymerase chain reaction in peripheral blood mononuclear cells (PBMCs). Results: In patients treated with IFN-β, tumor necrosis factor (TNF)-α production after exposure to TLR2 agonist (Pam₃Cys) was lower than in healthy controls and untreated MS patients. However, IFN-β treatment had no significant effect on TNF-α production after TLR4 agonist (LPS) stimulation. On the other hand, interleukin (IL)-10 production was increased in TLR4- but not in TLR2-stimulated whole-blood cell culture from MS patients under IFN-β treatment when compared to the controls. No differences in TNF-α or IL-10 mRNA expression in PBMCs from healthy controls and untreated or treated MS patients were detected, although PBMCs from treated patients presented higher levels of IL-32γ mRNA than those from controls. Conclusions: Our data suggest that IFN-β treatment alters the TLR-dependent immune response of PBMCs from MS patients. This may contribute to the beneficial effects of IFN-β treatment.

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TLR2 Stimulation Regulates the Balance between Regulatory T Cell and Th17 Function: A Novel Mechanism of Reduced Regulatory T Cell Function in Multiple Sclerosis

Cited by 64 publications

References 66 publications

Direct TLR-2 Costimulation Unmasks the Proinflammatory Potential of Neonatal CD4+ T Cells

Direct TLR-2 Costimulation Unmasks the Proinflammatory Potential of Neonatal CD4+ T Cells

TLR Tolerance as a Treatment for Central Nervous System Autoimmunity

Interferon-Beta Treatment Differentially Alters TLR2 and TLR4-Dependent Cytokine Production in Multiple Sclerosis Patients

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