Searching for the Achilles Heel of FOXP3

Lozano, Teresa; Casares, Noëlia; Lasarte, Juan José

doi:10.3389/fonc.2013.00294

Cited by 27 publications

(17 citation statements)

References 98 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Many of the functions of FOXP3 are clearly regulated by the interactions with these cofactors, contributing importantly to establishment of the Treg signature and also to FOXP3 functions (reviewed in Ref. 41). Among the increasing number of transcription factors able to bind to FOXP3, we have focused on NFAT/FOXP3 interaction, which has been shown to be crucial to repress expression of IL-2, upregulate expression of the Treg markers CTLA4 and CD25, and confer suppressor function (18).…”

Section: Discussionmentioning

confidence: 99%

Inhibition of FOXP3/NFAT Interaction Enhances T Cell Function after TCR Stimulation

Lozano

Villanueva

Durantez

et al. 2015

The Journal of Immunology

Self Cite

View full text Add to dashboard Cite

Regulatory T cell (Treg) activity is modulated by a cooperative complex between the transcription factor NFAT and FOXP3, a lineage specification factor for Tregs. FOXP3/NFAT interaction is required to repress expression of IL-2, upregulate expression of the Treg markers CTLA4 and CD25, and confer suppressor function to Tregs. However, FOXP3 is expressed transiently in conventional CD4+ T cells upon TCR stimulation and may lead to T cell hyporesponsiveness. We found that a short synthetic peptide able to inhibit FOXP3/NFAT interaction impaired suppressor activity of conventional Tregs in vitro. Specific inhibition of FOXP3/NFAT interaction with this inhibitory peptide revealed that FOXP3 downregulates NFAT-driven promoter activity of CD40L and IL-17. Inhibition of FOXP3/NFAT interaction upregulated CD40L expression on effector T cells and enhanced T cell proliferation and IL-2, IFN-γ, IL-6, or IL-17 production in response to TCR stimulation. The inhibitory peptide impaired effector T cell conversion into induced Tregs in the presence of TGF-β. Moreover, in vivo peptide administration showed antitumor efficacy in mice bearing Hepa129 or TC1 tumor cells when combined with sorafenib or with an antitumor vaccine, respectively. Our results suggest that inhibition of NFAT/FOXP3 interaction might improve antitumor immunotherapies.

show abstract

Section: Discussionmentioning

confidence: 99%

Inhibition of FOXP3/NFAT Interaction Enhances T Cell Function after TCR Stimulation

Lozano

Villanueva

Durantez

et al. 2015

The Journal of Immunology

Self Cite

View full text Add to dashboard Cite

show abstract

“…HIV transcriptional downregulation could be associated with NF-κB-dependent and -independent mechanisms ( 63 ), as well as to the Foxp3-dependent inhibition of NFAT activity. It was shown that Foxp3 decreases the binding of NFAT2 to the HIV promoter in vivo by its capacity to sequestrate it ( 61 , 64 ).…”

Section: Treg Immune-modulation and Mechanisms Of Actionmentioning

confidence: 99%

Functional Mechanisms of Treg in the Context of HIV Infection and the Janus Face of Immune Suppression

2016

View full text Add to dashboard Cite

Regulatory T cells (Tregs) play an important role in infections, by modulating host immune responses and avoiding the overreactive immunity that in the case of human immunodeficiency virus (HIV) infection leads to a marked erosion and deregulation of the entire immune system. Therefore, the suppressive function of Treg in HIV-infected patients is critical because of their implication on preventing the immune hyperactivation, even though it could also have a detrimental effect by suppressing HIV-specific immune responses. In recent years, several studies have shown that HIV-1 can directly infect Treg, disturbing their phenotype and suppressive capacity via different mechanisms. These effects include Foxp3 and CD25 downregulation, and the impairment of suppressive capacity. This review describes the functional mechanisms of Treg to modulate immune activation during HIV infection, and how such control is no longer fine-tune orchestrated once Treg itself get infected. We will review the current knowledge about the HIV effects on the Treg cytokine expression, on pathways implying the participation of different ectoenzymes (i.e., CD39/CD73 axis), transcription factors (ICER), and lastly on cyclic adenosine monophosphate (cAMP), one of the keystones in Treg-suppressive function. To define which are the HIV effects upon these regulatory mechanisms is crucial not only for the comprehension of immune deregulation in HIV-infected patients but also for the correct understanding of the role of Tregs in HIV infection.

show abstract

“…previous studies including ours on psoriasis and squamous cell carcinoma (10,16,17). However, few studies showed that the numbers of FOXP3 + Tregs were reduced or unchanged after UV irradiation (30,31). These differences may be explained by the individual difference, disease status or differences in UV exposure conditions.…”

Section: Discussionmentioning

confidence: 99%

Ultraviolet irradiation promotes FOXP3 transcription via p53 in psoriasis

Zhang

Chen

et al. 2016

Experimental Dermatology

View full text Add to dashboard Cite

The decrease of forkhead box P3-positive (FOXP3 + ) regulatory T cells (Tregs) causes an immune imbalance with effector T cells in psoriasis. Previous studies have demonstrated that in addition to its known effects on keratinocytes and effector T cells, ultraviolet (UV) irradiation alleviates psoriasis via the upregulation of FOXP3 + Tregs. However, the mechanism is unclear. Here, we found that FOXP3 + T cells were increased in psoriatic lesions after UVB irradiation (t' = 3.7006, P < 0.01), as determined by immunohistochemical staining. In addition, the levels of FOXP3 and p53, one of the downstream targets of UV irradiation, showed accordant changes after UV irradiation. Experiments that used a MAPK inhibitor, p53 mutant cell lines, p53 inhibitor and p53 shRNA showed a decrease in FOXP3 levels, suggesting that p53 is required for UV-induced FOXP3 transcription. Next, we demonstrated that there are two binding sites for p53 on FOXP3 by informatics tools, a dual-luciferase reporter assay and chromatin immunoprecipitation (ChIP) assay. One binding site (-1771 to -1583) is located at the promoter region and is adjacent to a previously reported p53-binding region in breast cancer cells. The other (+3845 to +4042) is located within the first intron and has not been previously reported. Our study demonstrated that FOXP3 is regulated, at least in part, by the binding of p53 to several binding sites in the promoter and intron regions following UV irradiation in psoriasis. It will be helpful to further clarify the regulatory mechanism of FOXP3 transcription and to provide new insights into the mechanisms that mediate the effects of UV irradiation in autoimmune skin disorders.

show abstract

Searching for the Achilles Heel of FOXP3

Cited by 27 publications

References 98 publications

Inhibition of FOXP3/NFAT Interaction Enhances T Cell Function after TCR Stimulation

Inhibition of FOXP3/NFAT Interaction Enhances T Cell Function after TCR Stimulation

Functional Mechanisms of Treg in the Context of HIV Infection and the Janus Face of Immune Suppression

Ultraviolet irradiation promotes FOXP3 transcription via p53 in psoriasis

Contact Info

Product

Resources

About