Reviews and feature articleT-cell effector pathways in allergic diseases: Transcriptional mechanisms and therapeutic targets
Section snippets
Transcriptional circuits and TH cell phenotype maintenance
The capacity of master regulatory factors to orchestrate TH cell differentiation is critically dependent on the induction by those factors of transcriptional circuits that establish the TH cell phenotype and maintain its stability. They also benefit from epigenetic changes that are brought about by the action of those circuits, and from the modular nature of TF domains, which allow 1 factor to simultaneously mediate interactions with DNA, other TFs, histones, and histone-modifying enzymes.9
Therapeutic strategies of targeting TFs
Transcription factors are the key regulators of immune responses and inflammation. Therefore, pharmacologic approaches of targeting TFs may be used as a strategy to treat diseases in the immune system, such as asthma. The strategies that modify the actions of TFs include direct blocking of their activation, interfering with their expression using nucleic acid–based technologies, and altering their interactions with other TFs.105 Here we present select examples of such approaches.
References (139)
Development in motion: helper T cells at work
Cell
(2007)- et al.
The many faces of the hygiene hypothesis
J Allergy Clin Immunol
(2006) - et al.
TGFbeta1, a “Jack of all trades”: the link with pro-inflammatory IL-17-producing T cells
Trends Immunol
(2006) - et al.
T helper cell differentiation: regulation by cis elements and epigenetics
Immunity
(2006) - et al.
A novel transcription factor, T-bet, directs Th1 lineage commitment
Cell
(2000) - et al.
Human tyrosine kinase 2 deficiency reveals its requisite roles in multiple cytokine signals involved in innate and acquired immunity
Immunity
(2006) - et al.
The transcription factor GATA-3 is necessary and sufficient for Th2 cytokine gene expression in CD4 T cells
Cell
(1997) - et al.
Transcription factor GATA-3 is differentially expressed in murine Th1 and Th2 cells and controls Th2-specific expression of the interleukin-5 gene
J Biol Chem
(1997) - et al.
Stat6-independent GATA-3 autoactivation directs IL-4-independent Th2 development and commitment
Immunity
(2000) - et al.
Inhibition of Th1 development mediated by GATA-3 through an IL-4-independent mechanism
Immunity
(1998)
Inhibition of allergic inflammation in a murine model of asthma by expression of a dominant-negative mutant of GATA-3
Immunity
Gene expression of the GATA-3 transcription factor is increased in atopic asthma
J Allergy Clin Immunol
Lentiviral-mediated GATA-3 RNAi decreases allergic airway inflammation and hyperresponsiveness
Mol Ther
The proto-oncogene c-maf is responsible for tissue-specific expression of interleukin-4
Cell
The transcription factor c-Maf controls the production of interleukin-4 but not other Th2 cytokines
Immunity
Role of regulatory T cells in human diseases
J Allergy Clin Immunol
Role of regulatory T cells and FOXP3 in human diseases
J Allergy Clin Immunol
Immune dysregulation, polyendocrinopathy, enteropathy, X-linked: forkhead box protein 3 mutations and lack of regulatory T cells
J Allergy Clin Immunol
CD25 deficiency causes an immune dysregulation, polyendocrinopathy, enteropathy, X-linked-like syndrome, and defective IL-10 expression from CD4 lymphocytes
J Allergy Clin Immunol
Scurfin (FOXP3) acts as a repressor of transcription and regulates T cell activation
J Biol Chem
FOXP3 controls regulatory T cell function through cooperation with NFAT
Cell
Foxp3 transcription-factor-dependent and -independent regulation of the regulatory T cell transcriptional signature
Immunity
The regulatory T cell transcriptosome: e pluribus unum
Immunity
Expression of interleukin-10 in intestinal lymphocytes detected by an interleukin-10 reporter knockin tiger mouse
Immunity
Th17: an effector CD4 T cell lineage with regulatory T cell ties
Immunity
The ROR nuclear orphan receptor subfamily: critical regulators of multiple biological processes
Prog Nucleic Acid Res Mol Biol
RORgamma t, a novel isoform of an orphan receptor, negatively regulates Fas ligand expression and IL-2 production in T cells
Immunity
The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17+ T helper cells
Cell
T helper 17 lineage differentiation is programmed by orphan nuclear receptors RORalpha and RORgamma
Immunity
Transcriptional regulation of Th17 cell differentiation
Semin Immunol
Two types of murine helper T cell clone, I: definition according to profiles of lymphokine activities and secreted proteins
J Immunol
A brief history of T(H)17, the first major revision in the T(H)1/T(H)2 hypothesis of T cell-mediated tissue damage
Nat Med
Regulatory T cells: a brief history and perspective
Eur J Immunol
Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells
Nature
Transforming growth factor-beta induces development of the T(H)17 lineage
Nature
Molecular mechanisms regulating Th1 immune responses
Annu Rev Immunol
Decision making in the immune system: the lineage decisions of helper T cells
Nat Rev Immunol
Control of effector CD8+ T cell function by the transcription factor eomesodermin
Science
Transcription factors T-bet and Runx3 cooperate to activate Ifng and silence Il4 in T helper type 1 cells
Nat Immunol
Hlx is induced by and genetically interacts with T-bet to promote heritable T(H)1 gene induction
Nat Immunol
T-bet's ability to regulate individual target genes requires the conserved T-box domain to recruit histone methyltransferase activity and a separate family member-specific transactivation domain
Mol Cell Biol
Transcriptional activators of helper T cell fate are required for establishment but not maintenance of signature cytokine expression
J Immunol
T-bet is a STAT1-induced regulator of IL-12R expression in naive CD4+ T cells
Nat Immunol
Role of T-bet in commitment of TH1 cells before IL-12-dependent selection
Science
T-bet regulates Th1 responses through essential effects on GATA-3 function rather than on IFNG gene acetylation and transcription
J Exp Med
Distinct effects of T-bet in TH1 lineage commitment and IFN-gamma production in CD4 and CD8 T cells
Science
Development of spontaneous airway changes consistent with human asthma in mice lacking T-bet
Science
Asthmatic changes in mice lacking T-bet are mediated by IL-13
Int Immunol
T-bet polymorphisms are associated with asthma and airway hyperresponsiveness
Am J Respir Crit Care Med
Host genetics of mycobacterial diseases in mice and men: forward genetic studies of BCG-osis and tuberculosis
Annu Rev Genomics Hum Genet
Cited by (50)
Hypersensitivity Reactions in the Respiratory Tract
2018, Comprehensive Toxicology: Third EditionA review on emerging frontiers of house dust mite and cockroach allergy research
2016, Allergologia et ImmunopathologiaMechanisms of allergen-specific immunotherapy and immune tolerance to allergens
2015, World Allergy Organization JournalCitation Excerpt :Based on their respective cytokine profiles, responses to chemokines and interactions with other cells, these T-cell subsets can promote different types of inflammatory responses. During the development of allergic disease, effector Th2 cells produce IL-4, IL-5, IL-9, IL-13 [35-37,65,66] and probably other recently identified cytokines such as IL-25, IL-31, IL-33 mainly secreted from epithelial cells and dendritic cells contribute to Th2 responses [67-73]. These cytokines play a role in the production of allergen-specific IgE, eosinophilia, permissiveness of endothelium for the recruitment of inflammatory cells to inflamed tissues, production of mucus and decreased threshold of contraction of smooth muscles [74].
Macelignan attenuated allergic lung inflammation and airway hyper-responsiveness in murine experimental asthma
2013, Life SciencesCitation Excerpt :In addition, we examined the levels of master transcription factors from subsets of Th cells from the lungs of macelignan-treated, allergen-challenged mice. Th1, Th2 and Th17 cells express distinct transcription factors such as T-bet, GATA3, and RORγt for differentiation and effector function, respectively (Chatila et al., 2008; Schmidt-Weber et al., 2007; Wells et al., 2007). Thus, we first investigated the mRNA expression of these master transcription factors with real-time RT-PCR.
Toxicity profile of the GATA-3-specific DNAzyme hgd40 after inhalation exposure
2013, Pulmonary Pharmacology and TherapeuticsMechanisms of allergen-specific immunotherapy
2011, Journal of Allergy and Clinical Immunology
(Supported by an educational grant from Merck & Co., Inc.)
Series editors: Joshua A. Boyce, MD, Fred Finkelman, MD, William T. Shearer, MD, PhD, and Donata Vercelli, MD
Supported by the National Institute of Allergy and Infectious Diseases–funded University of California at Los Angeles Asthma and Allergic Disease Clinical Research Center (U19 AI070453), a US Environmental Protection Agency (Science to Achieve Results) grant to the Southern California Particle Center, and National Institutes of Health grant 2R01AI065617 (T.A.C.).
Disclosure of potential conflict of interest: A. E. Nel has served as an expert witness in alleged rate effects of vaccine components and mold litigation. The rest of the authors have declared that they have no conflict of interest.
Terms in boldface and italics are defined in the glossary on page 813.