Functional type 1 regulatory T cells develop regardless of <i>FOXP3</i> mutations in patients with IPEX syndrome

Passerini, Laura; Nunzio, Sara Di; Gregori, Silvia; Gambineri, Eleonora; Cecconi, Massimiliano; Seidel, Markus G.; Cazzola, G; Perroni, L; Tommasini, Alberto; Vignola, Silvia; Guidi, L.; Roncarolo, Maria Grazia; Bacchetta, Rosa

doi:10.1002/eji.201040909

Cited by 74 publications

(51 citation statements)

References 44 publications

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“…Because IL-10-producing T cells do not rely on Foxp3 expression for their differentiation and function (34,35), these cells may contribute to the NRF2-mediated suppression of autoimmune responses in Sf mice, which are deficient in Foxp3. To examine this possibility, we measured the frequency of IL-10 ϩ CD4 ϩ T cells.…”

Section: Resultsmentioning

confidence: 99%

Systemic Activation of NRF2 Alleviates Lethal Autoimmune Inflammation in Scurfy Mice

Suzuki

Murakami

Biswal

et al. 2017

Molecular and Cellular Biology

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The transcription factor NRF2 (nuclear factor [erythroid-derived 2]-like 2) plays crucial roles in the defense mechanisms against oxidative stress and mediates anti-inflammatory actions under various pathological conditions. Recent studies showed that the dysfunction of regulatory T cells (Tregs) is directly linked to the initiation and progression of various autoimmune diseases. To determine the Tregindependent impact of NRF2 activation on autoimmune inflammation, we examined scurfy (Sf) mice, which are deficient in Tregs and succumb to severe multiorgan inflammation by 4 weeks of age. We found that systemic activation of NRF2 by Keap1 (Kelch-like ECH-associated protein 1) knockdown ameliorated tissue inflammation and lethality in Sf mice. Activated T cells and their cytokine production were accordingly decreased by Keap1 knockdown. In contrast, NRF2 activation through cell lineage-specific Keap1 disruption (i.e., in T cells, myeloid cells, and dendritic cells) achieved only partial or no improvement in the inflammatory status of Sf mice. Our results indicate that systemic activation of NRF2 suppresses effector T cell activities independently of Tregs and that NRF2 activation in multiple cell lineages appears to be required for sufficient anti-inflammatory effects. This study emphasizes the possible therapeutic application of NRF2 inducers in autoimmune diseases that are accompanied by Treg dysfunction.

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Section: Resultsmentioning

confidence: 99%

Systemic Activation of NRF2 Alleviates Lethal Autoimmune Inflammation in Scurfy Mice

Suzuki

Murakami

Biswal

et al. 2017

Molecular and Cellular Biology

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“…But it is not clear whether these autoantibodies play a pathogenic role for the development of diabetes. Studies of different animal and human models lacking with certain types of cells demonstrated that the lack of Tregs or impairment of their function lead to the development of autoimmune disease, including diabetes [24,25].…”

Section: T1d and Tregsmentioning

confidence: 99%

Immunotherapy in Autoimmune Diabetes

Haque¹,

Sandhu²,

Ravi³

et al. 2017

Immunopathogenesis and Immune-Based Therapy for Selected Autoimmune Disorders

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Autoimmune diabetes is a chronic autoimmune disease caused by the loss or selective destruction of the insulin-producing cells, called pancreatic beta cells. Damage to beta cells results in an absence or insufficient production of insulin produced by the body.Most cases of autoimmune diabetes have an autoimmune basis, and the immune system mistakenly attacks and destroys beta cells. The immune system plays a critical role in controlling the development of autoimmune diabetes. Over the past years there have been significant progress and an accumulation of scientific evidence for the concept of immunotherapy. Immunotherapy for the prevention and treatment of autoimmune diabetes has become the main focus of the research community. Three regimens of immunotherapy have been investigated: (1) Antigen-specific vaccines: Insulin-related molecules have attracted great interest in vaccine development, including the whole recombinant human GAD65 (rhGAD65) and the DiaPep277 peptide of HSP60. (2) Systemic immunomodulators: A large number of non-antigen-specific immunomodulators have been studied, including monoclonal anti-CD3 antibody, anti-CTLA-4 Ig, TNF-a, IFN-a, IL-1R antagonist, regulatory T cells, and dendritic cells. (3) Combination treatments: Combination therapies have the ability to enhance efficacy and will become the standard of care for autoimmune diabetes. Development of safe and efficient prevention of autoimmune diabetes is a general public health object in modern countries now. Although large numbers of preventive modalities including immunotherapy have been accomplished in animal models of autoimmune diabetes, prevention of human autoimmune diabetes remains indefinable. Genetic and environmental factors that control the relapsing-remitting course of β-cell destruction, terminating in complete insulin addiction are being determined. In the long run, initial prevention of islet autoimmunity will likely be the optimal approach to the prevention of autoimmune diabetes. However, environmental causes of islet autoimmunity need to be well stated. Modest predictive assessment of the existing genetic screening tools also means that the number of children requiring intervention will stay great, concerning the number of autoimmune diabetes cases prohibited. Nevertheless, combination treatments are more likely to be used for autoimmune diabetes. Primary systemic immunosuppression followed by antigen-specific induction of tolerance or islet regeneration is a sound approach.

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“…Indeed, functional Tr1 cells differentiate independently of FOXP3, thus suggesting that in favorable conditions, Tr1 cells could exert regulatory functions, which might compensate for the lack of tTreg dependent regulation especially in long-term surviving IPEX patients [62].…”

Section: Type 1 Regulatory T Cells In Ipex Patientsmentioning

confidence: 99%

Forkhead box P3:The Peacekeeper of the Immune System

Passerini¹,

Sio²,

Roncarolo³

et al. 2013

International Reviews of Immunology

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Ten years ago Forkhead box P3 (FOXP3) was discovered as master gene driving CD4+ CD25 + T cell regulatory (Treg) function. Since then, several layers of complexity have emerged in the regulation of its expression and function, which is not only exerted in Treg cells. While the mechanisms leading to the highly selective expression of FOXP3 in thymus-derived Treg cells still remain to be elucidated, we review here the current knowledge on the role of FOXP3 in the development of Treg cells and the direct and indirect consequences of FOXP3 mutations on multiple arms of the immune response. Finally, we summarize the newly acquired knowledge on the epigenetic regulation of FOXP3, still largely undefined in human cells.

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Functional type 1 regulatory T cells develop regardless of FOXP3 mutations in patients with IPEX syndrome

Cited by 74 publications

References 44 publications

Systemic Activation of NRF2 Alleviates Lethal Autoimmune Inflammation in Scurfy Mice

Systemic Activation of NRF2 Alleviates Lethal Autoimmune Inflammation in Scurfy Mice

Immunotherapy in Autoimmune Diabetes

Forkhead box P3:The Peacekeeper of the Immune System

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