Anti-TNF rescue CD4+Foxp3+ regulatory T cells in patients with type 1 diabetes from effects mediated by TNF

Ryba, Monika; Marek, Natalia; Hak, Łukasz; Rybarczyk-Kapturska, Karolina; Myśliwiec, Małgorzata; Trzonkowski, Piotr; Myśliwska, Jolanta

doi:10.1016/j.cyto.2011.05.006

Cited by 34 publications

(29 citation statements)

References 41 publications

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“…When TNFα was blocked by antibodies, the suppressive activity of Tregs was restored (30, 53) and this effect was shown to be TNFR2 dependent (31). Similar findings have been made in children with type 1 diabetes (55). Another study in patients infected with HBV reported that solTNFα partially abrogated Treg-mediated suppression of HBV-specific effector T cell responses (56).…”

Section: Discussionsupporting

confidence: 87%

Activated CD8+ T Cells Induce Expansion of Vβ5+ Regulatory T Cells via TNFR2 Signaling

Joedicke

Myers

Carmody

et al. 2014

The Journal of Immunology

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Vβ5+ regulatory T cells (Tregs), which are specific for a mouse endogenous retroviral superantigen, become activated and proliferate in response to Friend retrovirus (FV) infection. We previously reported that FV-induced expansion of this Treg subset was dependent on CD8+ T cells and TNFα, but independent of IL-2. We now show that the inflammatory milieu associated with FV infection is not necessary for induction of Vβ5+ Treg expansion. Rather, it is the presence of activated CD8+ T cells that is critical for their expansion. The data indicate that the mechanism involves signaling between the membrane-bound form of TNFα (memTNFα) on activated CD8+ T cells and TNF receptor 2 (TNFR2) on Tregs. CD8+ T cells expressing memTNFα but no soluble TNFα (solTNFα) remained competent to induce strong Vβ5+ Treg expansion in vivo. In addition, Vβ5+ Tregs expressing only TNFR2 but no TNFR1 were still responsive to expansion. Finally, treatment of naïve mice with solTNFα did not induce Vβ5+ Treg expansion, but treatment with a TNFR2-specific agonist did. These results reveal a new mechanism of intercellular communication between activated CD8+ T cell effectors and Tregs that results in the activation and expansion of a Treg subset that subsequently suppresses CD8+ T cell functions.

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Section: Discussionsupporting

confidence: 87%

Activated CD8+ T Cells Induce Expansion of Vβ5+ Regulatory T Cells via TNFR2 Signaling

Joedicke

Myers

Carmody

et al. 2014

The Journal of Immunology

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“…In line with these observations, decreased numbers of regulatory T-cells delineated by CD4+CD25+ phenotype were found in pediatric patients with T1D [9]. Lower percentages of CD4+CD127− (but not CD4+CD25+CD127−) T-cells were found in children with newly diagnosed T1D [10, 11]. Similarly, decreased frequencies of CD4+FoxP3+ cells were found in long-lasting T1D [12].…”

Section: Introductionmentioning

confidence: 81%

Decreased CD127 Expression on CD4+ T-Cells and Elevated Frequencies of CD4+CD25+CD127− T-Cells in Children with Long-Lasting Type 1 Diabetes

Moniuszko

Głowińska‐Olszewska

Rusak

et al. 2013

Clinical and Developmental Immunology

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Pathobiology of type 1 diabetes (T1D) is predominantly associated with T-cell-related actions. Homeostasis of majority of T-cells is critically dependent on signals mediated by CD127 (interleukin-7 receptor, IL-7R). In contrast, regulatory T-cells express very little CD127 and thereby may be delineated by CD4+CD25+CD127− phenotype. Here we aimed to analyze CD127 expression on CD4+ and CD8+ T-cells and enumerate CD4+CD25+CD127− T-cells in long-lasting T1D. T-cells were analyzed by flow cytometry and immunologic data were correlated with vascular, metabolic, and inflammatory parameters. We demonstrated significantly decreased CD127 levels on CD4+, but not CD8+, T cells in T1D pediatric patients. Interestingly, frequencies of CD4+CD25+CD127− T-cells were significantly enhanced in T1D children and correlated well with frequencies of CD34+CD144+ endothelial progenitor cells and CD4+CD25− T-cells. Levels of CD127 on both CD4+ and CD8+ T-cells in T1D patients were not correlated to each other or HbA1C. Interestingly, however, CD127 levels on CD4+ T-cells were significantly correlated to frequencies of CD4+CD25+CD127− T-cells, whereas CD127 levels on CD8+ T-cells were significantly correlated to concentrations of VEGF and triglycerides. Our data indicate that CD127 expression is differentially modulated on CD4+ and CD8+ T-cells in the course of T1D. Moreover, we demonstrated that, in contrast to recent-onset T1D, long-lasting T1D is associated with enhancement of T-cells with regulatory phenotype.

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“…Despite the above successes, TNF-targeted therapies sometimes have counter intuitive effects, and they have shown contradictory results in terms of efficacy (TABLE 1). For example, TNF inhibition has had a beneficial impact in children but not in older adults with T1D 139,140 , and on rare occasions, it has triggered new-onset T1D in patients who received TNFtargeted therapies for other inflammatory diseases 141,142 . As another example, although numerous studies have shown that TNF expression is enhanced in active lesions in patients with multiple sclerosis 143,144 , TNF inhibition in this group is detrimental 145,146 .…”

Section: Box 1 | Tnfr Signalling In Inflammatory Disordersmentioning

confidence: 99%

Regulation of tumour necrosis factor signalling: live or let die

2015

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Tumour necrosis factor (TNF) is a pro-inflammatory cytokine that has important roles in mammalian immunity and cellular homeostasis. Deregulation of TNF receptor (TNFR) signalling is associated with many inflammatory disorders, including various types of arthritis and inflammatory bowel disease, and targeting TNF has been an effective therapeutic strategy in these diseases. This Review focuses on the recent advances that have been made in understanding TNFR signalling and the consequences of its deregulation for cellular survival, apoptosis and regulated necrosis. We discuss how TNF-induced survival signals are distinguished from those that lead to cell death. Finally, we provide a brief overview of the role of TNF in inflammatory and autoimmune diseases, and we discuss up-to-date and future treatment strategies for these disorders.

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Anti-TNF rescue CD4+Foxp3+ regulatory T cells in patients with type 1 diabetes from effects mediated by TNF

Cited by 34 publications

References 41 publications

Activated CD8+ T Cells Induce Expansion of Vβ5+ Regulatory T Cells via TNFR2 Signaling

Activated CD8+ T Cells Induce Expansion of Vβ5+ Regulatory T Cells via TNFR2 Signaling

Decreased CD127 Expression on CD4+ T-Cells and Elevated Frequencies of CD4+CD25+CD127− T-Cells in Children with Long-Lasting Type 1 Diabetes

Regulation of tumour necrosis factor signalling: live or let die

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