FOXP3 ensembles in T‐cell regulation

Li, Bin; Samanta, Arabinda; Song, Xiaomin; Furuuchi, Keiji; Iacono, Kathryn T.; Kennedy, Sarah; Katsumata, Makoto; Saouaf, Sandra J.; Greene, Mark I.

doi:10.1111/j.0105-2896.2006.00405.x

Cited by 73 publications

(61 citation statements)

References 155 publications

(204 reference statements)

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“…We previously found that FOXP3 existed as a large complex independent of FOXP3 oligomerization (11), which led us to explore the possible role of FOXP3 as a positive transcriptional repressor. The repressor function is clearly further developed by recruitment of transcription corepressors such as HAT and HDAC.…”

Section: Discussionmentioning

confidence: 99%

“…FOXP3 may, for example, function as a passive transcriptional repressor in the case of its association with NFAT and NF-B (8,9). In this study, we explore the role of FOXP3 as an active transcriptional repressor by revealing the dynamic FOXP3 ensemble formation with a specific histone acetyltransferase (HAT) and certain class II histone deacetylases (HDACs) in expanded human CD4 ϩ CD25 ϩ regulatory T cells (10,11).…”

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confidence: 99%

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FOXP3 interactions with histone acetyltransferase and class II histone deacetylases are required for repression

Samanta

Song

et al. 2007

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

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The forkhead family protein FOXP3 acts as a repressor of transcription and is both an essential and sufficient regulator of the development and function of regulatory T cells. The molecular mechanism by which FOXP3-mediated transcriptional repression occurs remains unclear. Here, we report that transcriptional repression by FOXP3 involves a histone acetyltransferase-deacetylase complex that includes histone acetyltransferase TIP60 (Tat-interactive protein, 60 kDa) and class II histone deacetylases HDAC7 and HDAC9. The N-terminal 106 -190 aa of FOXP3 are required for TIP60 -FOXP3, HDAC7-FOXP3 association, as well as for the transcriptional repression of FOXP3 via its forkhead domain. FOXP3 can be acetylated in primary human regulatory T cells, and TIP60 promotes FOXP3 acetylation in vivo. Overexpression of TIP60 but not its histone acetyltransferase-deficient mutant promotes, whereas knockdown of endogenous TIP60 relieved, FOXP3-mediated transcriptional repression. A minimum FOXP3 ensemble containing native TIP60 and HDAC7 is necessary for IL-2 production regulation in T cells. Moreover, FOXP3 association with HDAC9 is antagonized by T cell stimulation and can be restored by the protein deacetylation inhibitor trichostatin A, indicating a complex dynamic aspect of T suppressor cell regulation. These findings identify a previously uncharacterized complex-based mechanism by which FOXP3 actively mediates transcriptional repression.A central theme that has emerged over the last 25 years is that a process of self-regulation of the immune response occurs to limit self-reactivity. Biochemical details of how the immune system distinguishes and regulates self and non-self remain to be fully documented (1). A recently characterized CD4 ϩ CD25 ϩ regulatory T cell subset expresses the Foxp3 transcription factor. As a transcriptional repressor of cytokine gene expression (2), Foxp3 was subsequently identified as an essential and sufficient regulator of natural regulatory T cell development and function (3-5).Mammalian transcriptional repressors can execute their function by either passive or active mechanisms (6, 7). FOXP3 may, for example, function as a passive transcriptional repressor in the case of its association with 9). In this study, we explore the role of FOXP3 as an active transcriptional repressor by revealing the dynamic FOXP3 ensemble formation with a specific histone acetyltransferase (HAT) and certain class II histone deacetylases (HDACs) in expanded human CD4 ϩ CD25 ϩ regulatory T cells (10, 11).Histone acetylation and histone deacetylation affect chromatin remodeling during T cell development and differentiation (12, 13). HAT and HDAC abnormalities have been associated with leukemia (14, 15), diabetes (16) and other diseases of the immune system (17-19). The linkage of HAT and HDAC as components of a single complex permits dynamic responsiveness to extracellular stimulation (18,20). The HAT TIP60 (Tat-interactive protein, 60 kDa), originally isolated as an HIV-1 TAT-interactive protein (21), functions as eith...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

FOXP3 interactions with histone acetyltransferase and class II histone deacetylases are required for repression

Samanta

Song

et al. 2007

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

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369

374

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“…31,53-60 FOXP3 forms part of a large protein complex that regulates the expression of hallmark genes associated with Treg cell phenotype. [61][62][63][64] The genomic region of the Foxp3 locus has several conserved non-coding sequences (CNS1, CNS2 and CNS3) that play different roles in the regulation of Foxp3 transcription. CNS1 contains binding sites for NFAT and AP-1 and is essential for peripheral, but not thymic, induction of FOXP3 expression.…”

Section: Mechanisms Underlying the Suppressive Function Of Foxp3 1 Trmentioning

confidence: 99%

FOXP3+ regulatory T cells and their functional regulation

et al. 2015

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“…Activated T CD4+CD25 low cells are probably the source of IL-2 in peripheral tissues in vivo (18). Antagonizing of Treg function could be obtained by signalling through GITR on the surface of effector T cells which is mediated by GITR ligand (GITR-L) on DCs' surface, or alternatively by secretion of IL-6 produced by activated DCs (19,20). Treg cells produce soluble GITR (sGITR) molecules which could interfere with GITR-L on DCs and block GITR/GITR-L interactions thus providing enhancement of suppression by Tregs (21).…”

Section: Phenotype and Function Of Natural Tregsmentioning

confidence: 99%

The characterization and role of regulatory T cells in immune reactions

Jacek¹

2008

Front Biosci

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FOXP3 ensembles in T‐cell regulation

Cited by 73 publications

References 155 publications

FOXP3 interactions with histone acetyltransferase and class II histone deacetylases are required for repression

FOXP3 interactions with histone acetyltransferase and class II histone deacetylases are required for repression

FOXP3+ regulatory T cells and their functional regulation

The characterization and role of regulatory T cells in immune reactions

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