{Reference Type}: Journal Article
{Title}: TOX promotes follicular helper T cell differentiation in patients with primary Sjögren's syndrome.
{Author}: Liu S;Yang Y;Zeng L;Wang L;He C;Chen Z;Sun J;Lyu T;Wang M;Chen H;Zhang F;
{Journal}: Rheumatology (Oxford)
{Volume}: 62
{Issue}: 2
{Year}: 02 2023 1
{Factor}: 7.046
{DOI}: 10.1093/rheumatology/keac304
{Abstract}: Whether naive CD4+ T cells are dysregulated and associated with the overactivation of CD4+ T cells in primary SS (pSS) remains unclear. We aimed to explore the role and underlying mechanism of naive CD4+ T cells in pSS.<BR>We examined the activation, proliferation and differentiation of naive CD4+ T cells from pSS patients and healthy controls. Differentially expressed genes were identified using RNA sequencing, and were overexpressed or silenced to determine the gene regulating follicular helper T (Tfh) cells. Assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-seq) with chromatin immunoprecipitation with high-throughput sequencing (ChIP-seq) was performed to explore the epigenetic mechanism. Naive CD4+ T cells were treated with pSS-related cytokines to explore the upstream signalling pathway.<BR>pSS naive CD4+ T cells had higher potentials of activation, proliferation and differentiation towards Tfh cells. Thymocyte selection-associated high mobility group box protein (TOX) was upregulated in pSS naive CD4+ T cells and promoted T cell activation and Tfh cell polarization. TOX silencing in pSS naive CD4+ T cells downregulated B cell lymphoma 6 (BCL6) expression and altered levels of multiple Tfh-associated genes. ChIP-seq analysis implied that TOX bound to the BCL6 locus, where there were accessible regions found by ATAC-seq. IFN-α induced TOX overexpression, which was attenuated by Janus kinase (JAK) and signal transducer and activator of transcription 1 (STAT1) inhibitors.<BR>Our data suggest that TOX in pSS naive CD4+ T cells is upregulated, which facilitates Tfh cell differentiation. Mechanistically, IFN-α induces TOX overexpression in naive CD4+ T cells through JAK-STAT1 signalling and TOX regulates BCL6 expression. Therefore, IFN-α-JAK-STAT1 signalling and TOX might be potential therapeutic targets in pSS.