Stabilizing Human Regulatory T Cells for Tolerance Inducing Immunotherapy

He, Xiaotian; Koenen, Hans J. P. M.; Slaats, Jeroen; Joosten, Irma

doi:10.2217/imt-2017-0017

Cited by 9 publications

(8 citation statements)

References 169 publications

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“…To exert their suppressive function, Treg stability, and therefore stable FOXP3 expression is imperative. The stability of Treg is currently the topic of many studies in the Treg field (4). Importantly, besides the loss of suppressive function, Treg can differentiate into proinflammatory cytokine-producing cells (also named exTreg) under specific microenvironmental cues, and induce detrimental immune responses, posing a threat for adoptive Treg therapies.…”

Section: Metabolic Pathways Linked To Treg Behavior and Functionmentioning

confidence: 99%

“…Treg modulate the immune system both specifically and aspecifically via inhibition of dendritic cell function and maturation, secretion of anti-inflammatory cytokines, and suppression of induction and proliferation of antigen-specific effector T cells (Teff) (3), depicted in Figure 1. As reviewed previously (4), human Treg are characterized by expression of the transcription factor Forkhead box p3 (FOXP3) and the combination of cell surface markers CD4 + , CD25 + , and CD127 low/− . FOXP3 is the most reliable cell marker for Treg, although it is also transiently expressed by activated effector T cells.…”

Section: Introductionmentioning

confidence: 99%

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Metabolic Pathways Involved in Regulatory T Cell Functionality

et al. 2019

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Regulatory T cells (Treg) are well-known for their immune regulatory potential and are essential for maintaining immune homeostasis. The rationale of Treg-based immunotherapy for treating autoimmunity and transplant rejection is to tip the immune balance of effector T cell-mediated immune activation and Treg-mediated immune inhibition in favor of Treg cells, either through endogenous Treg expansion strategies or adoptive transfer of ex vivo expanded Treg. Compelling evidence indicates that Treg show properties of phenotypic heterogeneity and instability, which has caused considerable debate in the field regarding their correct use. Consequently, for further optimization of Treg-based immunotherapy, it is vital to further our understanding of Treg proliferative, migratory, and suppressive behavior. It is increasingly appreciated that the functional profile of immune cells is highly dependent on their metabolic state. Although the metabolic profiles of effector T cells are progressively understood, little is known on Treg in this respect. The objective of this review is to outline the current knowledge of human Treg metabolic profiles associated with the regulation of Treg functionality. As such information on human Treg is still limited, where information was lacking, we included insightful findings from mouse studies. To assess the available evidence on metabolic pathways involved in Treg functionality, PubMed, and Embase were searched for articles in English indexed before April 28th, 2019 using “regulatory T lymphocyte,” “cell metabolism,” “cell proliferation,” “migration,” “suppressor function,” and related search terms. Removal of duplicates and search of the references was performed manually. We discerned that while glycolysis fuels the biosynthetic and bioenergetic needs necessary for proliferation and migration of human Treg, suppressive capacity is mainly maintained by oxidative metabolism. Based on the knowledge of metabolic differences between Treg and non-Treg cells, we additionally discuss and propose ways of how human Treg metabolism could be exploited for the betterment of tolerance-inducing therapies.

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Section: Metabolic Pathways Linked To Treg Behavior and Functionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Metabolic Pathways Involved in Regulatory T Cell Functionality

et al. 2019

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“…MicroRNAs are fundamental in Treg development and function. miR-155, miR-15b/16, miR-24, and miR-29a were described as important players in Treg differentiation and maintenance [ 23 , 88 ].…”

Section: Micrornas As a New Mechanism Of Suppression By Tregsmentioning

confidence: 99%

Immunological Mechanisms in Allergic Diseases and Allergen Tolerance: The Role of Treg Cells

Calzada

Baos

Cremades-Jimeno

et al. 2018

Journal of Immunology Research

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The immune system regulates itself to establish an appropriate immune response to potentially harmful pathogens while tolerating harmless environmental antigens and self-antigens. A central role in this balance is played by regulatory T cells (Tregs) through various ways of actions. By means of molecule secretion and cell-cell contact mechanisms, Tregs may have the capacity to modulate effector T cells and suppress the action of proinflammatory cytokines across a broad range of cell types. As a result, abnormal regulatory T cell function has been pointed as a main cause in the development of allergic diseases, a major public health problem in industrialized countries, with a high socioeconomic impact. This prevalence and impact have created an international interest in improving the allergy diagnosis and therapy. Additionally, research has sought to gain a better understanding of the molecular mechanisms underlining this kind of disease, in order to a better management. At this respect, the role of Treg cells is one of the most promising areas of research, mainly because of their potential use as new immunotherapeutical approaches. Therefore, the aim of this review is to update the existing knowledge of the role of Tregs in this pathology deepening in their implication in allergen-specific therapy (AIT).

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“…The stable expression of Foxp3 and the maintenance of Treg stability are critical for their suppressive function [ 118 ]. The stimulation of suppressive molecules on Tregs, including CTLA-4 and PD-1, increased the expression of Foxp3, which directly inhibited the PI3K-Akt-mTORC1 axis and caused a decrease in glycolysis and increases in OXPHOS and FAO (Fig.…”

Section: Metabolic Determinants For Treg Proliferation Migration and ...mentioning

confidence: 99%

Metabolic profiles of regulatory T cells and their adaptations to the tumor microenvironment: implications for antitumor immunity

et al. 2022

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Characterized by the expression of the critical transcription factor forkhead box protein P3, regulatory T (Treg) cells are an essential part of the immune system, with a dual effect on the pathogenesis of autoimmune diseases and cancer. Targeting Tregs to reestablish the proinflammatory and immunogenic tumor microenvironment (TME) is an increasingly attractive strategy for cancer treatment and has been emphasized in recent years. However, attempts have been significantly hindered by the subsequent autoimmunity after Treg ablation owing to systemic loss of their suppressive capacity. Cellular metabolic reprogramming is acknowledged as a hallmark of cancer, and emerging evidence suggests that elucidating the underlying mechanisms of how intratumoral Tregs acquire metabolic fitness and superior immunosuppression in the TME may contribute to clinical benefits. In this review, we discuss the common and distinct metabolic profiles of Tregs in peripheral tissues and the TME, as well as the differences between Tregs and other conventional T cells in their metabolic preferences. By focusing on the critical roles of different metabolic programs, such as glycolysis, oxidative phosphorylation, fatty acid oxidation, fatty acid synthesis, and amino acid metabolism, as well as their essential regulators in modulating Treg proliferation, migration, and function, we hope to provide new insights into Treg cell-targeted antitumor immunotherapies.

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Stabilizing Human Regulatory T Cells for Tolerance Inducing Immunotherapy

Cited by 9 publications

References 169 publications

Metabolic Pathways Involved in Regulatory T Cell Functionality

Metabolic Pathways Involved in Regulatory T Cell Functionality

Immunological Mechanisms in Allergic Diseases and Allergen Tolerance: The Role of Treg Cells

Metabolic profiles of regulatory T cells and their adaptations to the tumor microenvironment: implications for antitumor immunity

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