It takes 2 TOXes to Tfh Tango

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Science Immunology  06 Dec 2019:
Vol. 4, Issue 42, eaba3067
DOI: 10.1126/sciimmunol.aba3067


TOX and TOX2 promote T follicular helper cell development through transcriptional changes and epigenetic remodeling.

T follicular helper (Tfh) cells are a subset of CD4+ T cells that provide help to cognate germinal center B cells. Several transcription factors (TFs) have been found to be crucial for Tfh cell development, notably BCL6, as well as BATF, IRF4, and TCF1. Xu et al. sought to identify additional TFs that specify Tfh cell identity by looking for BCL6-regulated genes. They found that family members TOX and TOX2 are more highly expressed in Tfh cells as compared to other CD4+ T cell subsets. These TFs have recently come to prominence for their roles in promoting CD8+ T cell exhaustion during chronic infection or cancer. In CD8+ T cells, TOX induces the expression of TCF1 (Tcf7) and inhibitory receptors such as PD1 (Pdcd1), while also suppressing effector functions. These changes allow for a more durable T cell response and mitigate immunopathology. In the current study, TOX or TOX2 overexpression in CD4+ T cells led to increased expression of Tfh cell-associated genes, including Tcf7, Pdcd1, Bcl6 and Cxcr5, and thus greater Tfh cell differentiation. Many of these genes harbored TOX2 binding sites by ChIP-seq, indicating potentially direct transcriptional activation by TOX2. TOX2 overexpression promoted increased binding by other Tfh cell TFs, suggesting that TOX2 also acts to remodel the chromatin landscape during Tfh cell differentiation. This is concordant with the epigenetic remodeling capabilities of TOX in CD8+ T cells. Combined TOX and TOX2 deficiency was required to abrogate Tfh cell differentiation and impair germinal center B cells, demonstrating functional redundancy between the two TOX family members. These recent studies provide an interesting juxtaposition of TOX and TOX2 function in CD4+ versus CD8+ T cells. While inducing similar target genes (e.g., Tcf7, Pdcd1), previous studies together with this current one indicate that TOX and TOX2 promote disparate outcomes in these two chronically antigen-exposed—increased effector function of CD4+ Tfh cells and reduced effector function of CD8+ T cells. More studies on the TOX TFs may provide insight into how they differentially regulate effector fate in different immune cells.

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