Transcription factor interplay in T helper cell differentiation

Evans, Catherine M.; Jenner, Richard G.

doi:10.1093/bfgp/elt025

Cited by 84 publications

(89 citation statements)

References 96 publications

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“…CD4+ T cell phenotypes are more diverse and flexible than previously appreciated (15). CD4+ T cells cytokine profiles can evolve upon changing environmental conditions and ‘mixed’ phenotypes characterized by co-expression of multiple transcription factors have been reported (reviewed in (16-18)). This suggests that transcription factors regulate lineage commitment as a network rather than as unique determinants (19-21).…”

Section: Introductionmentioning

confidence: 99%

HIV Skews the Lineage-Defining Transcriptional Profile of Mycobacterium tuberculosis–Specific CD4+ T Cells

Riou

Strickland

Soares

et al. 2016

The Journal of Immunology

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HIV-infected persons are at greater risk of developing tuberculosis (TB) even before profound CD4 loss occurs, suggesting that HIV alters CD4+T cell functions capable of containing bacterial replication. An effective immune response to Mycobacterium tuberculosis likely relies on the development of a balanced CD4 response, where distinct CD4+T helper subsets act in synergy to control the infection. To define the diversity of Mtb-specific CD4+Th subsets and determine whether HIV infection impacts such responses, the expression of lineage-defining transcription factors T-bet, Gata3, RORγt and Foxp3 was measured in Mtb-specific CD4+T cells in HIV-uninfected (n=20) and HIV-infected individuals (n=20) with latent TB infection. Our results show that upon 5 day restimulation in vitro, Mtb-specific CD4+T cells from healthy individuals have the ability to exhibit a broad spectrum of T helper subsets, defined by specific patterns of transcription factor co-expression. These transcription factor profiles were skewed in HIV-infected individuals where the proportion of T-bethighFoxp3+ Mtb-specific CD4+T cells was significantly decreased (p=0.002) compared to HIV-uninfected individuals, a change that correlated inversely with HIV viral load (p=0.0007) and plasma TNF-α (p=0.027). Our data demonstrate an important balance in T helper subset diversity defined by lineage-defining transcription factor co-expression profiles that is disrupted by HIV infection and suggest a role for HIV in impairing TB immunity by altering the equilibrium of Mtb-specific CD4+T helper subsets.

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Section: Introductionmentioning

confidence: 99%

HIV Skews the Lineage-Defining Transcriptional Profile of Mycobacterium tuberculosis–Specific CD4+ T Cells

Riou

Strickland

Soares

et al. 2016

The Journal of Immunology

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“…12,13,18 Functionally, Th1 and Th2 cells inhibit each other at the level of the transcription factors, with Th17 and Treg cells similarly inhibiting one another. 19,20 Although a few studies have investigated transcription factors among HT patients, few have measured Th1/Th2, Th1/Treg, Th2/Treg and Th17/ Treg cell balances at the level of these transcription factors. 21,22 This study therefore aimed to determine the balance of effector T cells-specifically, Th1, Th2, Th17 and Treg cells-at the level of transcription factors by measuring the expression of their master transcription factors-T-bet, GATA 3 , RORα/RORγt and FOXP3, respectively-and determining their ratios in the peripheral blood mononuclear cells (PBMCs) of HT patients in comparison to healthy individuals.…”

mentioning

confidence: 99%

Imbalances in T Cell-Related Transcription Factors Among Patients with Hashimoto’s Thyroiditis

Safdari¹,

Alijani²,

Nemati³

et al. 2017

SQUMJ

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abstract:Objectives: Imbalances in effector T cell functioning have been associated with a number of autoimmune diseases, including Hashimoto's thyroiditis (HT). Differentiation of effector T helper (Th) 1, Th2, Th17 and regulatory T cell (Treg) lymphocytes is regulated by transcription factors, including Th1-specific T box (T-bet), GATA binding protein-3 (GATA 3 ), retinoid-related orphan receptor (ROR)-α and forkhead box P3 (FOXP3). This study aimed to investigate Th1/Th2, Th1/Treg, Th2/Treg and Th17/Treg balances at the level of these transcription factors. Methods: This study took place between October 2015 and August 2016. Peripheral blood mononuclear cells were collected from a control group of 40 healthy women recruited from the Zahedan University of Medical Sciences, Zahedan, Iran, and a patient group of 40 women with HT referred to the Hazrat Ali Asghar Hospital, Zahedan. Total ribonucleic acid extraction was performed and the gene expression of transcription factors was quantitated using a real-time polymerase chain reaction technique. Results: Expression of T-bet and GATA 3 was significantly elevated, while FOXP3 expression was significantly diminished among HT patients in comparison with the controls (P = 0.03, 0.01 and 0.05, respectively). Expression of RORα was higher among HT patients, although this difference was not significant (P = 0.15). Expression of T-bet/FOXP3, GATA 3 /FOXP3 and RORα/FOXP3 ratios were increased among HT patients in comparison with the controls (P <0.02, <0.01 and <0.01, respectively). Conclusion: These results indicate that HT patients have imbalances in Th1/Treg, Th2/Treg and Th17/Treg lymphocytes at the level of the transcription factors, deviating towards Th1, Th2 and Th17 cells. Correction of these imbalances may therefore be therapeutic. Keywords

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“…44). CD4 + T-cell lineage commitment is determined by the cytokine composition of the microenvironment in which the CD4 + T cells are primed and boosted via transcriptional regulation of lineage-specific cytokine gene families (38,39,45). This observation leads to the sobering possibility that CD4 + CCR5 + T cells (i.e., Th17 cells) responding to an HIV vaccine designed to elicit a persistent and protective antibody response could blunt protection or, worse, increase susceptibility to infection, as suggested in the adenovirus serotype 5 (Ad5) vaccine trials (13)(14)(15)(16).…”

mentioning

confidence: 99%

Antibody persistence and T-cell balance: Two key factors confronting HIV vaccine development

Lewis

DeVico

Gallo

2014

Proc. Natl. Acad. Sci. U.S.A.

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The quest for a prophylactic AIDS vaccine is ongoing, but it is now clear that the successful vaccine must elicit protective antibody responses. Accordingly, intense efforts are underway to identify immunogens that elicit these responses. Regardless of the mechanism of antibodymediated protection, be it neutralization, Fc-mediated effector function, or both, antibody persistence and appropriate T-cell help are significant problems confronting the development of a successful AIDS vaccine. Here, we discuss the evidence illustrating the poor persistence of antibody responses to Env, the envelope glycoprotein of HIV-1, and the related problem of CD4 + T-cell responses that compromise vaccine efficacy by creating excess cellular targets of HIV-1 infection. Finally, we propose solutions to both problems that are applicable to all Envbased AIDS vaccines regardless of the mechanism of antibody-mediated protection.

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Transcription factor interplay in T helper cell differentiation

Cited by 84 publications

References 96 publications

HIV Skews the Lineage-Defining Transcriptional Profile of Mycobacterium tuberculosis–Specific CD4+ T Cells

HIV Skews the Lineage-Defining Transcriptional Profile of Mycobacterium tuberculosis–Specific CD4+ T Cells

Imbalances in T Cell-Related Transcription Factors Among Patients with Hashimoto’s Thyroiditis

Antibody persistence and T-cell balance: Two key factors confronting HIV vaccine development

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