STAT6-Dependent Regulation of Th9 Development

Goswami, Ritobrata; Jabeen, Rukhsana; Yagi, Ryoji; Pham, Duy; Zhu, Jinfang; Goenka, Shreevrat; Kaplan, Mark H.

doi:10.4049/jimmunol.1102840

Cited by 211 publications

(249 citation statements)

References 39 publications

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“…Nonetheless, TGF-β/IL-15 had a more significant negative impact on TBX21 (T-bet) and EOMES gene expression and T-bet protein expression, which were both further down-regulated in the presence of CD28 costimulation (A/E beads). Such a negative effect of TGF-β on T-bet (34) might foster Th9 differentiation, because it also has been shown that T-bet counteracts the development of IL-9-secreting cells (35). Moreover, in response to TGF-β/IL-15, Vδ2 T cells up-regulated Eos and, in line with published data (23,24), FoxP3.…”

Section: Discussionsupporting

confidence: 75%

Human Vδ2 T cells are a major source of interleukin-9

Peters

Häsler

Wesch

et al. 2016

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

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Vδ2Vγ9 T cells are the dominant γδ T-cell subset in human peripheral blood. Vδ2 T cells recognize pyrophosphate molecules derived from microbes or tumor cells; hence, they play a role in antimicrobial and antitumor immunity. TGF-β, together with IL-15, induces a regulatory phenotype in Vδ2 T cells, characterized by forkhead box protein P3 (FoxP3) expression and suppressive activity on CD4 T-cell activation. We performed a genome-wide transcriptome analysis and found that the same conditions (TGF-β plus IL-15) strongly enhanced the expression of additional genes in Vδ2 T cells, including IKAROS family zinc finger 4 (IKZF4; Eos), integrin subunit alpha E (ITGAE; CD103/αEβ7), and IL9. This up-regulation was associated with potent IL-9 production as revealed by flow cytometry and multiplex analysis of cell culture supernatants. In contrast to CD4 and CD8 αβ T cells, γδ T cells did not require IL-4 for induction of intracellular IL-9 expression. Upon antigen restimulation of Vδ2 T cells expanded in vitro in the presence of TGF-β and IL-15, IL-9 was the most abundant among 16 analyzed cytokines and chemokines. IL-9 is a pleiotropic cytokine involved in various (patho)physiological conditions, including allergy and tumor defense, where it can promote antitumor immunity. Given the conspicuous sensitivity of many different tumors to Vδ2 T-cell–mediated killing, the conditions defined here for strong induction of IL-9 might be relevant for the development of Vδ2 T-cell–based immunotherapy.

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Section: Discussionsupporting

confidence: 75%

Human Vδ2 T cells are a major source of interleukin-9

Peters

Häsler

Wesch

et al. 2016

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

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“…Accordingly, the generation of Th9 cells was absent in STAT6-deficient and GATA3-deficient mice, which confirmed that STAT6 and GATA3 were essential in the generation of Th9 cells (9). However, some data demonstrate that GATA3 is not directly involved in the transcriptional regulation of the il9 gene, but acts rather as a molecule involved in the downregulation of Foxp3, a protein that could negatively affect Th9 development (21).…”

Section: Transcriptional Program Of Th9 Cellsmentioning

confidence: 66%

“…Moreover, the ectopic expression of Foxp3 reduces IL9 production by Th9 cells (21), thus demonstrating a negative effect of Foxp3 on Th9 differentiation. TGFb induces the activation of the SMAD pathway and the expression of PU.1, which could restrain Th2 polarization (22).…”

Section: Transcriptional Program Of Th9 Cellsmentioning

confidence: 99%

Th9 Cells: A Novel CD4 T-cell Subset in the Immune War against Cancer

2015

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CD4 T cells are key components of the immune system that shape the anticancer immune response in animal models and in humans. The biology of CD4 T cells is complex because na€ ve T cells can differentiate into various subpopulations with various functions. Recently, a new population called Th9 cells was described. These cells are characterized by their ability to produce IL9 and IL21. They were first described in the context of parasite infections and allergic processes. However, some reports described their presence in the tumor bed in mice and humans. Their high secretion of IL9 and IL21 in the tumor bed contributes to their anticancer functions. Indeed, these cytokines trigger the activation of dendritic cells, mast cells, natural killer cells, and CD8 T cells to mount an antitumor immune response, thus explaining the remarkable ability of Th9 cells to control tumor growth. This review summarizes the latest advances in the Th9 field in cancer and focuses on their potential role as new tool for cell therapy. Cancer Res; 75(3); 475-9. Ó2014 AACR. The Role of CD4 T-cell Polarization in CancerSince the seminal observations of Dunn and colleagues (1) on cancer immunosurveillance, the role of the adaptive immune system in the development of cancer or tumor growth is clearly established. CD4 helper T cells are key elements of the adaptive immune response, and are known to differentiate from a na€ ve population into helper memory populations after stimulation by T-cell receptor (TCR) triggering by the cognate antigen and a particular cocktail of cytokines. The original classification of CD4 T lymphocytes by Mosmann and Colleagues (2) described two populations of effector CD4 T cells called Th1 and Th2 subsets. Th1 are IFNg-producing cells and were known as the classical antitumor cells because of the capacity of IFNg to activate the killer functions of macrophages, natural killer (NK) cells, and CD8 CTLs. Th2 cells are characterized by their production of IL4, and play a central role in the development of asthma and atopic dermatitis. The role of Th2 cells in cancer is mainly deleterious as IL4 directly favors tumor growth. In addition, Th2 cells could induce M2 polarization of tumor-infiltrating macrophages, which drive tumor immune tolerance and neoangiogenesis (3). CD4 T cells are now known to differentiate into additional new effector T-cell subsets like Th17 cells and follicular helper T cells as well as immunosuppressive cells like Foxp3 regulatory T cells. Foxp3 regulatory T cells are well-known immunosuppressive cells. These cells inhibit the anticancer immune response and induce immunosuppression in many cancer types (4). In contrast, the infiltration of tumors by follicular helper T cells seems to be associated with a coordinated antitumoral immune response and a better clinical outcome (5). The role of Th17 cells in cancer remains a matter of debate. IL17 could promote neoangiogenesis and the expression of prosurvival genes in cancer cells (6). In addition, ectonucleotidase-expressing Th17 cells co...

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“…In general, selective cytokine receptor or SOCS protein expression serves as a major buffer to resist cytokine-driven repolarization of T cells, although DNA accessibility (discussed next) also has a crucial role. Second, the so-called 'master regulators' or 'lineage-defining' transcription factors T-bet, GATAbinding protein 3 (GATA3), RORγt, BCL-6 and FOXP3 have a substantial, but often incomplete, role in setting the transcriptional programmes of T H 1, T H 2, T H 17, T FH and T Reg cells, respectively 62,[113][114][115] . The capacity for these transcription factors to directly antagonize each other's functions through direct protein-protein interactions may impart coherency in effector responses 11,116 (FIG.…”

Section: Box 2 | Phenotypic Plasticity In Inflammatory and Regulatorymentioning

confidence: 99%

Harnessing the plasticity of CD4+ T cells to treat immune-mediated disease

2016

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| CD4 + T cells differentiate and acquire distinct functions to combat specific pathogens but can also adapt their functions in response to changing circumstances. Although this phenotypic plasticity can be potentially deleterious, driving immune pathology, it also provides important benefits that have led to its evolutionary preservation. Here, we review CD4 + T cell plasticity by examining the molecular mechanisms that regulate it -from the extracellular cues that initiate and drive cells towards varying phenotypes, to the cytosolic signalling cascades that decipher these cues and transmit them into the cell and to the nucleus, where these signals imprint specific gene expression programmes. By understanding how this functional flexibility is achieved, we may open doors to new therapeutic approaches that harness this property of T cells.

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STAT6-Dependent Regulation of Th9 Development

Cited by 211 publications

References 39 publications

Human Vδ2 T cells are a major source of interleukin-9

Human Vδ2 T cells are a major source of interleukin-9

Th9 Cells: A Novel CD4 T-cell Subset in the Immune War against Cancer

Harnessing the plasticity of CD4+ T cells to treat immune-mediated disease

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