A Mutation in the Transcription Factor Foxp3 Drives T Helper 2 Effector Function in Regulatory T Cells

Gool, Frédéric Van; Nguyen, Michelle; Mumbach, Maxwell R.; Satpathy, Ansuman T.; Rosenthal, Wendy; Giacometti, Simone; Le, Duy T.; Liu, Weihong; Brusko, Todd M.; Anderson, Mark S.; Rudensky, Alexander Y.; Marson, Alexander; Chang, Howard Y.; Bluestone, Jeffrey A.

doi:10.1016/j.immuni.2018.12.016

Cited by 86 publications

(58 citation statements)

References 56 publications

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“…Some FOXP3 mutations cause less severe diseases. For example, patients with a point mutation in the domain swap interface of FOXP3 protein develop a Th2-related disease [202]. In addition to Foxp3 mutations, deficiency in other regulators of Treg-suppressive functions, such as TRAF3 [203], CD28 [204], Id2/Id3 [205], Ubc13 [206], Ndfip1 [207], NF-κB p65 [208], Helios [209], Th-POK/LRF [210], EZH2 [211], BACH2 [212,213], SATB1 [214], IRF-4 and Blimp-1 [215], and LKB1 [216], can also result in severe autoimmune diseases, although most of these studies were carried out in mice, and their relevance in human diseases remains to be tested.…”

Section: Treg Related Diseasesmentioning

confidence: 99%

CD4 T Helper Cell Subsets and Related Human Immunological Disorders

Zhu

2020

IJMS

224

138

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The immune system plays a critical role in protecting hosts from the invasion of organisms. CD4 T cells, as a key component of the immune system, are central in orchestrating adaptive immune responses. After decades of investigation, five major CD4 T helper cell (Th) subsets have been identified: Th1, Th2, Th17, Treg (T regulatory), and Tfh (follicular T helper) cells. Th1 cells, defined by the expression of lineage cytokine interferon (IFN)-γ and the master transcription factor T-bet, participate in type 1 immune responses to intracellular pathogens such as mycobacterial species and viruses; Th2 cells, defined by the expression of lineage cytokines interleukin (IL)-4/IL-5/IL-13 and the master transcription factor GAΤA3, participate in type 2 immune responses to larger extracellular pathogens such as helminths; Th17 cells, defined by the expression of lineage cytokines IL-17/IL-22 and the master transcription factor RORγt, participate in type 3 immune responses to extracellular pathogens including some bacteria and fungi; Tfh cells, by producing IL-21 and expressing Bcl6, help B cells produce corresponding antibodies; whereas Foxp3-expressing Treg cells, unlike Th1/Th2/Th17/Tfh exerting their effector functions, regulate immune responses to maintain immune cell homeostasis and prevent immunopathology. Interestingly, innate lymphoid cells (ILCs) have been found to mimic the functions of three major effector CD4 T helper subsets (Th1, Th2, and Th17) and thus can also be divided into three major subsets: ILC1s, ILC2s, and ILC3s. In this review, we will discuss the differentiation and functions of each CD4 T helper cell subset in the context of ILCs and human diseases associated with the dysregulation of these lymphocyte subsets particularly caused by monogenic mutations.

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Section: Treg Related Diseasesmentioning

confidence: 99%

CD4 T Helper Cell Subsets and Related Human Immunological Disorders

Zhu

2020

IJMS

224

138

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“…They have also been shown to be resistant to immunosuppressive treatment with dexamethasone in asthmatic patients in contrast to classic Th2 cells . Defects in the key transcription factor FoxP3 in murine Treg cells result in the reduction of Treg cell regulatory functions and induce a Th2‐like phenotype, highlighting the plasticity among T‐cell lineages . Despite extensive evidence for the reciprocal molecular regulation of Th1 and Th2 cells, hybrid IL‐4 and IFN‐γ positive T cells exist that resist reprogramming into either classic Th1 or Th2 cells in humans and mice .…”

Section: Blurring Borders Among Th1 Th2 and Th17 Traitsmentioning

confidence: 99%

Shaping the diversity of Th2 cell responses in epithelial tissues and its potential for allergy treatment

Matthias

Zielinski

2019

Eur J Immunol

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Th2 cells have evolved to protect from large helminth infections and to exert tissue protective functions in response to nonmicrobial noxious stimuli. The initiation, maintenance, and execution of these functions depend on the integration of diverse polarizing cues by cellular sensors and molecular programs as well as the collaboration with cells that are coopted for signal exchange. The complexity of input signals and cellular collaboration generates tissue specific Th2 cell heterogeneity and specialization. In this review, we aim to discuss the advances and recent breakthroughs in our understanding of Th2 cell responses and highlight developmental and functional differences among T cells within the diversifying field of type 2 immunity. We will focus on factors provided by the tissue microenvironment and highlight factors with potential implications for the pathogenesis of allergic skin and lung diseases. Especially new insights into the role of immunometabolism, the microbiota and ionic signals enhance the complexity of Th2 cell regulation and warrant a critical evaluation. Finally, we will discuss how this ensemble of established knowledge and recent breakthroughs about Th2 immunobiology advance our understanding of the pathogenesis of allergic diseases and how this could be exploited for future immunotherapies.Keywords: Th2 cells r allergy r sodium chloride r metabolism r immunotherapy

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“…These cells also dampen host antitumor immunity, decreasing the efficacy of tumor immune surveillance (3). The key transcription factor Foxp3 has a critical role in the differentiation and function of Tregs (4,5), and knockdown or mutations of Foxp3 attenuate the immunosuppressive capacity of Tregs (6,7). Similarly, depletion of Foxp3 + CD4 + Tregs results in severe autoimmunity in otherwise normal animals and can be reversed by reconstituting Tregs (8,9).…”

Section: Introductionmentioning

confidence: 99%