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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE136538 | GEO | 2019/10/30

REPOSITORIES: GEO

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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.

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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

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2014-12-22 | GSE58589 | GEO

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Project description:Follicular helper T (Tfh) cells are essential for generating protective humoral immunity. To date, microRNAs (miRNAs) have emerged as important players in regulating Tfh cell biology. Here, we show that loss of miR-23~27~24 clusters in T cells resulted in elevated Tfh cell frequencies upon different immune challenges whereas overexpression of this miRNA family led to reduced Tfh cell responses. Mechanistically, miR-23~27~24 clusters coordinately control Tfh cells through targeting a network of genes that are crucial for Tfh cell biology. Among them, thymocyte selection-associated HMG-box protein (TOX) was identified as a central transcription regulator in Tfh cell development. TOX is highly up-regulated in both mouse and human Tfh cells in a BCL6-dependent manner. In turn, TOX promotes the expression of multiple molecules that play critical roles in Tfh cell differentiation and function. Collectively, our study on miR-23~27~24-mediated control of humoral immunity reveals a TOX-driven regulatory circuit in orchestrating Tfh cell responses.

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TOX induces T cell IL-10 production in a BATF-dependent manner

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