Transcription factors Foxo3a and Foxo1 couple the E3 ligase Cbl-b to the induction of Foxp3 expression in induced regulatory T cells

Harada, Yohsuke; Harada, Yasuyo; Elly, Chris; Ge, Ying; Paik, Jihye; DePinho, Ronald A.; Liu, Yun‐Cai

doi:10.1083/jcb1894oia11

Cited by 67 publications

(105 citation statements)

References 32 publications

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“…At the same time, robust antigen receptor and cytokine receptor stimulation activates PI3K, which negatively regulates FoxP3 expression (3,4). This occurs when PI3K activates protein kinase B (PKB), which in turn phosphorylates and inactivates forkhead-box O (Foxo) transcription factors that promote FoxP3 expression (5)(6)(7). Consistent with this model, conditional deletion of Foxo1 and Foxo3 results in reduced numbers of thymic-and peripheral-derived Tregs (7,8).…”

mentioning

confidence: 82%

KLF2 is a rate-limiting transcription factor that can be targeted to enhance regulatory T-cell production

Kumar

Rabacal

Maseda

et al. 2014

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

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Regulatory T cells (Tregs) are a specialized subset of CD4 + T cells that maintain self-tolerance by functionally suppressing autoreactive lymphocytes. The Treg compartment is composed of thymus-derived Tregs (tTregs) and peripheral Tregs (pTregs) that are generated in secondary lymphoid organs after exposure to antigen and specific cytokines, such as TGF-β. With regard to this latter lineage, pTregs [and their ex vivo generated counterparts, induced Tregs (iTregs)] offer particular therapeutic potential because these cells can be raised against specific antigens to limit autoimmunity. We now report that transcription factor Krüppel-like factor 2 (KLF2) is necessary for the generation of iTregs but not tTregs. Moreover, drugs that limit KLF2 proteolysis during T-cell activation enhance iTreg development. To the authors' knowledge, this study identifies the first transcription factor to distinguish between i/pTreg and tTreg ontogeny and demonstrates that KLF2 is a therapeutic target for the production of regulatory T cells.

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mentioning

confidence: 82%

KLF2 is a rate-limiting transcription factor that can be targeted to enhance regulatory T-cell production

Kumar

Rabacal

Maseda

et al. 2014

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

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“…For instance, PKB directly phosphorylates FoxO1 and FoxO3 [37,38], leading to their cytoplasmic retention thus inhibiting its nuclear transcriptional activity [45]. This further dampens FoxO-dependent transcriptional regulation of T-bet [46,47] and FoxP3 [47][48][49][50][51]. Helper T cell differentiation is accompanied by the activation of unique metabolic programs.…”

Section: Immune Cell Intrinsic Role Of Pkb In Motility Activation Dmentioning

confidence: 99%

PKB/Akt-dependent regulation of inflammation in cancer

Tang

Wang

Hemmings

et al. 2018

Seminars in Cancer Biology

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A B S T R A C TChronic inflammation is a major cause of human cancer. Clinical cancer therapies against inflammatory risk factors are strategically determined. To rationally guide a novel drug development, an improved mechanistic understanding on the pathological connection between inflammation and carcinogenesis is essential. PI3K-PKB signaling axis has been extensively studied and shown to be one of the key oncogenic drivers in most types of cancer. Pharmacological inhibition of the components along this signaling axis is of great interest for developing novel therapies. Interestingly, emerging studies have shown a close association between PKB activation and inflammatory activity in the vicinity of the tumor, and either blockade of PKB or attenuation of para-tumoral inflammation reveals a mutual-interactive pattern through pathway crosstalk. In this review, we intend to discuss recent advances of PKB-regulated chronic inflammation and its potential impacts on tumor development.

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“…Taken together, these data indicate that AnxA1 does not directly induce differentiation of niT cells, but it may facilitate the transfer of neutrophil-derived signaling proteins necessary for niT-cell formation. The transcription factor FOXO1 is the master regulator necessary for FOXP3 expression in inducible Tregs (34)(35)(36). Intriguingly, FOXO1 is expressed by neutrophils, where it is endowed with proapoptotic functions (37).…”

Section: Depletion Of Neutrophils During Pregnancy Leads To Impaired mentioning

confidence: 99%

Neutrophils induce proangiogenic T cells with a regulatory phenotype in pregnancy

Nadkarni

Sferruzzi‐Perri

et al. 2016

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

120

117

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Although neutrophils are known to be fundamental in controlling innate immune responses, their role in regulating adaptive immunity is just starting to be appreciated. We report that human neutrophils exposed to pregnancy hormones progesterone and estriol promote the establishment of maternal tolerance through the induction of a population of CD4+ T cells displaying a GARP+CD127loFOXP3+ phenotype following antigen activation. Neutrophil-induced T (niT) cells produce IL-10, IL-17, and VEGF and promote vessel growth in vitro. Neutrophil depletion during murine pregnancy leads to abnormal development of the fetal-maternal unit and reduced empbryo development, with placental architecture displaying poor trophoblast invasion and spiral artery development in the maternal decidua, accompanied by significantly attenuated niT cell numbers in draining lymph nodes. Using CD45 congenic cells, we show that induction of niT cells and their regulatory function occurs via transfer of apoptotic neutrophil-derived proteins, including forkhead box protein 1 (FOXO1), to T cells. Unlike in women with healthy pregnancies, neutrophils from blood and placental samples of preeclamptic women fail to induce niT cells as a direct consequence of their inability to transfer FOXO1 to T cells. Finally, neutrophil-selective FOXO1 knockdown leads to defective placentation and compromised embryo development, similar to that resulting from neutrophil depletion. These data define a nonredundant function of neutrophil–T cell interactions in the regulation of vascularization at the maternal–fetal interface.

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Transcription factors Foxo3a and Foxo1 couple the E3 ligase Cbl-b to the induction of Foxp3 expression in induced regulatory T cells

Abstract: CORRESPONDENCEYun-Cai Liu: yuncail@liai.org Abbreviations used: iT reg cell, induced T reg cell; mTOR, mammalian target of rapamycin; nT reg cell, naturally occuring T reg cell; PI3K, phosphoinositide 3-kinase; T eff, effector T cell; T reg cell, regulatory T cell. Transcription factors

Cited by 67 publications

References 32 publications

KLF2 is a rate-limiting transcription factor that can be targeted to enhance regulatory T-cell production

KLF2 is a rate-limiting transcription factor that can be targeted to enhance regulatory T-cell production

PKB/Akt-dependent regulation of inflammation in cancer

Neutrophils induce proangiogenic T cells with a regulatory phenotype in pregnancy

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