HTLV-1 bZIP Factor Induces Inflammation through Labile Foxp3 Expression

Abstract Human T-cell leukemia virus type 1 (HTLV-1) is an oncogenic retrovirus that is etiologically associated with adult T-cell leukemia. The HTLV-1 bZIP factor (HBZ), which is encoded by the minus strand of the provirus, is involved in both regulation of viral gene transcription and T-cell proliferation. We showed in this report that HBZ interacted with Smad2/3, and enhanced transforming growth factor-β (TGF-β)/Smad transcriptional responses in a p300-dependent manner. The N-terminal LXXLL motif of HBZ was responsible for HBZ-mediated TGF-β signaling activation. In a serial immunoprecipitation assay, HBZ, Smad3, and p300 formed a ternary complex, and the association between Smad3 and p300 was markedly enhanced in the presence of HBZ. In addition, HBZ could overcome the repression of the TGF-β response by Tax. Finally, HBZ expression resulted in enhanced transcription of Pdgfb, Sox4, Ctgf, Foxp3, Runx1, and Tsc22d1 genes and suppression of the Id2 gene; such effects were similar to those by TGF-β. In particular, HBZ induced Foxp3 expression in naive T cells through Smad3-dependent TGF-β signaling. Our results suggest that HBZ, by enhancing TGF-β signaling and Foxp3 expression, enables HTLV-1 to convert infected T cells into regulatory T cells, which is thought to be a critical strategy for virus persistence.

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Faculty Opinions recommendation of TGF-beta1 maintains suppressor function and Foxp3 expression in CD4+CD25+ regulatory T cells.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1009275.325095 ◽

2005 ◽

Author(s):

Thomas Huenig

Keyword(s):

T Cells ◽

Regulatory T Cells ◽

Foxp3 Expression ◽

Suppressor Function

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Faculty Opinions recommendation of Cutting edge: TCR stimulation is sufficient for induction of Foxp3 expression in the absence of DNA methyltransferase 1.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.719461140.793554127 ◽

2018 ◽

Author(s):

Daniel Mueller

Keyword(s):

Dna Methyltransferase ◽

Foxp3 Expression ◽

Cutting Edge ◽

Dna Methyltransferase 1 ◽

Methyltransferase 1

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Faculty Opinions recommendation of Crying Time and RORγ/FOXP3 Expression in Lactobacillus reuteri DSM17938-Treated Infants with Colic: A Randomized Trial.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.731685320.793562117 ◽

2019 ◽

Author(s):

Harald Brüssow

Keyword(s):

Randomized Trial ◽

Lactobacillus Reuteri ◽

Foxp3 Expression

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Synthesis and Inhibitory Effects of Some Novel 1,3-diarylprop-2-en-1-one Analogues in Foxp3 Expression: A Novel Class of Anti-cancer Candidates

Medicinal Chemistry ◽

10.2174/15734064113099990029 ◽

2013 ◽

Vol 9 (8) ◽

pp. 1035-1040 ◽

Cited By ~ 1

Author(s):

Mayank Kinger ◽

Jeong Park ◽

Min Hur ◽

Sang Kim ◽

Seung Yang

Keyword(s):

Foxp3 Expression ◽

Inhibitory Effects ◽

Anti Cancer

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Efficient IL-2R signaling differentially affects the stability, function, and composition of the regulatory T-cell pool

Cellular and Molecular Immunology ◽

10.1038/s41423-020-00599-z ◽

2021 ◽

Author(s):

Marc Permanyer ◽

Berislav Bošnjak ◽

Silke Glage ◽

Michaela Friedrichsen ◽

Stefan Floess ◽

...

Keyword(s):

T Cell ◽

Treg Cell ◽

Cell Function ◽

Interleukin 2 ◽

Foxp3 Expression ◽

Treg Cells ◽

Receptor Expression ◽

Spontaneous Mutant ◽

Cell Pool ◽

And Function

AbstractSignaling via interleukin-2 receptor (IL-2R) is a requisite for regulatory T (Treg) cell identity and function. However, it is not completely understood to what degree IL-2R signaling is required for Treg cell homeostasis, lineage stability and function in both resting and inflammatory conditions. Here, we characterized a spontaneous mutant mouse strain endowed with a hypomorphic Tyr129His variant of CD25, the α-chain of IL-2R, which resulted in diminished receptor expression and reduced IL-2R signaling. Under noninflammatory conditions, Cd25Y129H mice harbored substantially lower numbers of peripheral Treg cells with stable Foxp3 expression that prevented the development of spontaneous autoimmune disease. In contrast, Cd25Y129H Treg cells failed to efficiently induce immune suppression and lost lineage commitment in a T-cell transfer colitis model, indicating that unimpaired IL-2R signaling is critical for Treg cell function in inflammatory environments. Moreover, single-cell RNA sequencing of Treg cells revealed that impaired IL-2R signaling profoundly affected the balance of central and effector Treg cell subsets. Thus, partial loss of IL-2R signaling differentially interferes with the maintenance, heterogeneity, and suppressive function of the Treg cell pool.

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Secretome screening reveals immunomodulating functions of IFNα-7, PAP and GDF-7 on regulatory T-cells

Scientific Reports ◽

10.1038/s41598-021-96184-z ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Mei Ding ◽

Rajneesh Malhotra ◽

Tomas Ottosson ◽

Magnus Lundqvist ◽

Aman Mebrahtu ◽

...

Keyword(s):

T Cells ◽

Regulatory T Cells ◽

Cell Function ◽

Foxp3 Expression ◽

Treg Cells ◽

Secreted Proteins ◽

External Stimulation ◽

Marker Proteins ◽

Positive Regulators ◽

Conformational Model

AbstractRegulatory T cells (Tregs) are the key cells regulating peripheral autoreactive T lymphocytes. Tregs exert their function by suppressing effector T cells. Tregs have been shown to play essential roles in the control of a variety of physiological and pathological immune responses. However, Tregs are unstable and can lose the expression of FOXP3 and suppressive functions as a consequence of outer stimuli. Available literature suggests that secreted proteins regulate Treg functional states, such as differentiation, proliferation and suppressive function. Identification of secreted proteins that affect Treg cell function are highly interesting for both therapeutic and diagnostic purposes in either hyperactive or immunosuppressed populations. Here, we report a phenotypic screening of a human secretome library in human Treg cells utilising a high throughput flow cytometry technology. Screening a library of 575 secreted proteins allowed us to identify proteins stabilising or destabilising the Treg phenotype as suggested by changes in expression of Treg marker proteins FOXP3 and/or CTLA4. Four proteins including GDF-7, IL-10, PAP and IFNα-7 were identified as positive regulators that increased FOXP3 and/or CTLA4 expression. PAP is a phosphatase. A catalytic-dead version of the protein did not induce an increase in FOXP3 expression. Ten interferon proteins were identified as negative regulators that reduced the expression of both CTLA4 and FOXP3, without affecting cell viability. A transcriptomics analysis supported the differential effect on Tregs of IFNα-7 versus other IFNα proteins, indicating differences in JAK/STAT signaling. A conformational model experiment confirmed a tenfold reduction in IFNAR-mediated ISG transcription for IFNα-7 compared to IFNα-10. This further strengthened the theory of a shift in downstream messaging upon external stimulation. As a summary, we have identified four positive regulators of FOXP3 and/or CTLA4 expression. Further exploration of these Treg modulators and their method of action has the potential to aid the discovery of novel therapies for both autoimmune and infectious diseases as well as for cancer.

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Tolerogenic Splenic IDO+Dendritic Cells from the Mice Treated with Induced-Treg Cells Suppress Collagen-Induced Arthritis

Journal of Immunology Research ◽

10.1155/2014/831054 ◽

2014 ◽

Vol 2014 ◽

pp. 1-12 ◽

Cited By ~ 9

Author(s):

Jie Yang ◽

Yiming Yang ◽

Huahua Fan ◽

Hejian Zou

Keyword(s):

Dendritic Cells ◽

Immune Responses ◽

Foxp3 Expression ◽

Treated Group ◽

Treg Cells ◽

Therapeutic Effects ◽

Dependent Manner ◽

Collagen Induced Arthritis

TGF-β-induced regulatory T cells (iTregs) retain Foxp3 expression and immune-suppressive activity in collagen-induced arthritis (CIA). However, the mechanisms whereby transferred iTregs suppress immune responses, particularly the interplay between iTregs and dendritic cells (DCs)in vivo, remain incompletely understood. In this study, we found that after treatment with iTregs, splenic CD11c+DCs, termed “DCiTreg,” expressed tolerogenic phenotypes, secreted high levels of IL-10, TGF-β, and IDO, and showed potent immunosuppressive activityin vitro. After reinfusion with DCiTreg, marked antiarthritic activity improved clinical scores and histological end-points were observed. The serological levels of inflammatory cytokines and anti-CII antibodies were low and TGF-βproduction was high in the DCiTreg-treated group. DCiTregalso induced new iTregsin vivo. Moreover, the inhibitory activity of DCiTregon CIA was lost following pretreatment with the inhibitor of indoleamine 2,3-dioxygenase (IDO). Collectively, these findings suggest that transferred iTregs could induce tolerogenic characteristics in splenic DCs and these cells could effectively dampen CIA in an IDO-dependent manner. Thus, the potential therapeutic effects of iTregs in CIA are likely maintained through the generation of tolerogenic DCsin vivo.

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FOXP3 expression accurately defines the population of intratumoral regulatory T cells that selectively accumulate in metastatic melanoma lesions

Blood ◽

10.1182/blood-2008-06-163048 ◽

2008 ◽

Vol 112 (13) ◽

pp. 4953-4960 ◽

Cited By ~ 98

Author(s):

Mojgan Ahmadzadeh ◽

Aloisio Felipe-Silva ◽

Bianca Heemskerk ◽

Daniel J. Powell ◽

John R. Wunderlich ◽

...

Keyword(s):

T Cells ◽

Tumor Microenvironment ◽

Metastatic Melanoma ◽

Treg Cell ◽

Peripheral Blood ◽

Ex Vivo ◽

Production Capacity ◽

Biological Marker ◽

Foxp3 Expression ◽

Treg Cells

Abstract Regulatory T (Treg) cells are often found in human tumors; however, their functional characteristics have been difficult to evaluate due to low cell numbers and the inability to adequately distinguish between activated and Treg cell populations. Using a novel approach, we examined the intracellular cytokine production capacity of tumor-infiltrating T cells in the single-cell suspensions of enzymatically digested tumors to differentiate Treg cells from effector T cells. Similar to Treg cells in the peripheral blood of healthy individuals, tumor-infiltrating FOXP3+CD4 T cells, unlike FOXP3− T cells, were unable to produce IL-2 and IFN-γ upon ex vivo stimulation, indicating that FOXP3 expression is a valid biological marker for human Treg cells even in the tumor microenvironment. Accordingly, we enumerated FOXP3+CD4 Treg cells in intratumoral and peritumoral sections of metastatic melanoma tumors and found a significant increase in proportion of FOXP3+CD4 Treg cells in the intratumoral compared with peritumoral areas. Moreover, their frequencies were 3- to 5-fold higher in tumors than in peripheral blood from the same patients or healthy donors, respectively. These findings demonstrate that the tumor-infiltrating CD4 Treg cell population is accurately depicted by FOXP3 expression, they selectively accumulate in tumors, and their frequency in peripheral blood does not properly reflect tumor microenvironment.

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