GSE136537
Global gene expression profile of CD4+ T cells activated and infected with Tox2- or GFP-only virus under different conditions (RNA-Seq)
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. Overall design: To gain insights into the mechanism whereby Tox2 regulates Tfh differentiation, we performed RNA-seq analysis on Tox2-overexpressing (Tox2-RV-GFP+) and control (Empty-RV-GFP+) CD4+ T cells cultured in both Th0 (aIFN?+aIL-4+aIL-2) and Tfh-like (aIFN?+aIL-4+aIL-2+IL-6) conditions.