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TOX2 coordinates with TET2 to positively regulate central memory differentiation in human CAR T cells

ABSTRACT: To investigate the effects of TOX and TOX2 on memory T cell differentiation in human CAR T cells, we used shRNA to knock down TOX2 or TOX, or overexpress FLAG-TOX2. We then performed gene expression profiling analysis using RNAseq, plus examined the binding of TOX2 to chromatin using ChIPseq.

ORGANISM(S): Homo sapiens

PROVIDER: GSE231620 | GEO | 2023/07/24

REPOSITORIES: GEO

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TOX2 coordinates with TET2 to positively regulate central memory differentiation in human CAR T cells.

Project description:Chimeric antigen receptor (CAR) T cell therapy is used in treating human hematological malignancies, but its efficacy is limited by T cell exhaustion (TEX). TEX arises at the expense of central memory T cells (TCM), which exhibit robust antitumor efficacy. Reduction of the TET2 gene led to increased TCM differentiation in a patient with leukemia who experienced a complete remission. We show that loss of TET2 led to increased chromatin accessibility at exhaustion regulators TOX and TOX2, plus increased expression of TOX2. Knockdown of TOX increased the percentage of TCM. However, unexpectedly, knockdown of TOX2 decreased TCM percentage and reduced proliferation. Consistently, a TCM gene signature was reduced in the TOX2 knockdown, and TOX2 bound to promoters of numerous TCM genes. Our results thus suggest a role for human TOX2, in contrast to exhaustion regulator TOX, as a potentiator of central memory differentiation of CAR T cells, with plausible utility in CAR T cell cancer therapy via modulated TOX2 expression.

| S-EPMC10355826 | biostudies-literature

TOX2 regulates human natural killer cell development by controlling T-BET expression

Project description:Thymocyte selection-associated high mobility group box protein family member 2 (TOX2) is a transcription factor belonging to the TOX family that shares a highly conserved high mobility group DNA binding domain with the other TOX members. While TOX1 has been shown to be an essential regulator of T-cell and natural killer (NK) cell differentiation in mice, little is known about the roles of the other TOX family members in lymphocyte development, particularly in humans. In this study, we found that TOX2 was preferentially expressed in mature human NK cells and was upregulated during in vitro differentiation of NK cells from human umbilical cord blood (UCB)M-bM-^@M-^Sderived CD34+ cells. Gene silencing of TOX2 intrinsically hindered the transition between early developmental stages of NK cells, while overexpression of TOX2 enhanced the development of mature NK cells from UCB CD34+ cells. We subsequently found that TOX2 was independent of ETS-1 but could directly upregulate the transcription of TBX21 (encoding T-BET). Overexpression of T-BET rescued the TOX2 knockdown phenotypes. Given the essential function of T-BET in NK cell differentiation, TOX2 therefore plays a crucial role in controlling normal NK cell development by acting upstream of TBX21 transcriptional regulation. survey of NK cells over time

2014-12-22 | E-GEOD-58589 | biostudies-arrayexpress

TOX2 regulates human natural killer cell development by controlling T-BET expression

Project description:Thymocyte selection-associated high mobility group box protein family member 2 (TOX2) is a transcription factor belonging to the TOX family that shares a highly conserved high mobility group DNA binding domain with the other TOX members. While TOX1 has been shown to be an essential regulator of T-cell and natural killer (NK) cell differentiation in mice, little is known about the roles of the other TOX family members in lymphocyte development, particularly in humans. In this study, we found that TOX2 was preferentially expressed in mature human NK cells and was upregulated during in vitro differentiation of NK cells from human umbilical cord blood (UCB)–derived CD34+ cells. Gene silencing of TOX2 intrinsically hindered the transition between early developmental stages of NK cells, while overexpression of TOX2 enhanced the development of mature NK cells from UCB CD34+ cells. We subsequently found that TOX2 was independent of ETS-1 but could directly upregulate the transcription of TBX21 (encoding T-BET). Overexpression of T-BET rescued the TOX2 knockdown phenotypes. Given the essential function of T-BET in NK cell differentiation, TOX2 therefore plays a crucial role in controlling normal NK cell development by acting upstream of TBX21 transcriptional regulation.

2014-12-22 | GSE58589 | GEO

TOX2 coordinates with TET2 to positively regulate central memory differentiation in human CAR T cells

Project description:TOX2 coordinates with TET2 to positively regulate central memory differentiation in human CAR T cells

| PRJNA967021 | ENA

Distruption of TOX and TOX2 transcription factors in CAR T cells limits T cell exhaustion [ATAC-Seq]

Project description:We comapre mRNA expression level TOX and TOX2 CAR TILS and WT CAR TILs

2019-05-31 | GSE130539 | GEO

Distruption of TOX and TOX2 transcription factors in CAR T cells limits T cell exhaustion [RNA-Seq]

Project description:We comapre mRNA expression level TOX and TOX2 CAR TILS and WT CAR TILs

2019-05-31 | GSE130538 | GEO

Genome binding/occupancy profiling of Tox2 in Tfh-like cells

Project description:T Follicular helper (Tfh) cell is an effector CD4+ T cell subset specialized in helping B cells in germinal centers (GC) reactions. Although Bcl6 was identified as a Tfh-specific transcription factor essential for their development, the molecular mechanisms underlying Bcl6 regulation and Tfh cell commitment remain unclear. Here, we report that Tox2 transcription factor is highly expressed in Tfh cells, regulated by Bcl6 and STAT3. Forced expression of Tox2 drives Bcl6 expression and Tfh development. Mechanistically, Tox2 directly binds to Tfh-associated genes, including Bcl6, and functions to promote their chromatin accessibility and modulate the activities of other Tfh-regulating factors. Conversely, genetic deletion of Tox2 results in defective Tfh differentiation, and inhibiting both Tox and Tox2 in T cells abolishes Tfh differentiation and GC response. Thus, our results demonstrate that Tox2 is a key transcription factor that regulates Bcl6 expression and Tfh development and suggest a Tox2-Bcl6 axis in feed-forward regulation of Tfh program.

2019-10-30 | GSE136539 | GEO

Transcription factor Tox2 functions to promote chromatin remodeling during T follicular helper (Tfh) cell development (ATAC-seq)

2019-10-30 | GSE136538 | GEO

Global gene expression profile of CD4+ T cells activated and infected with Tox2- or GFP-only virus under different conditions (RNA-Seq)

2019-10-30 | GSE136537 | GEO

Transcription Factor Tox2 is required for Follicular Helper T Cells differentiation

Project description:Follicular helper T (Tfh) cells are crucial for formation of B cell germinal center (GC) and long-term production of antigen-specific antibodies. The molecular mechanism underlying Tfh cell differentiation, however, still remains largely unknown. Here, we show that the transcription factor Thymocyte selection-associated high mobility group box family member 2 (Tox2) is important for Tfh cell development. Tox2 deficiency led to impaired Tfh cell differentiation and subsequently reduced GC formation. Consistently, ectopic expression of Tox2 promoted Tfh cell differentiation. Mechanistically, we found that Tox2 regulated the expression of Ascl2, an initiator in driving CXCR5 transcription in Tfh cells; Tox2 deficiency caused the decreased expression of Ascl2. Restoration of Ascl2 expression in Tox2 deficient CD4+ T cells rescued the defect in Tfh cell differentiation. Our study suggests that Tox2 is an important transcription factor for Tfh cell development.

2020-06-01 | GSE136694 | GEO

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