Differential BCL6-mediated transcriptional regulation of human TFH cells 2300

Abstract Description Although B-cell lymphoma 6 (BCL6) has been known as the lineage-defining transcription factor (TF) of T follicular helper (TFH) cells, the details of the mechanistic functions of BCL6 in human T cells have not been explored. Here, a CRISPR-screen on primary human CD4+ T cells to disrupt TF genes of interest in in vitro differentiated TFH cells, we report the regulatory role of BCL6 and its downstream TF network in humans. Out of 283 TFs initially considered, top 10 hits were also disrupted in memory-TFH cells ex vivo. Reciprocally inhibitory type-1 associated genes previously known to exert antagonistic effects on BCL6 activity in mice were confirmed, including Prdm1 (encoding BLIMP1). Multiple novel BCL6 target genes, distinct from those previously established in mice, were validated to contribute significantly to TFH differentiation or function. Many of these genes act upstream of BCL6 to shape early T cell commitment and epigenetic remodeling by maintaining reciprocally inhibitory relationships with BCL6. Several of these newly identified transcriptional regulators exerted greater repressive effects on BCL6 expression and TFH function than BLIMP1 in the in vitro human TFH differentiation conditions used. Taken together, the present work identifies novel regulatory players within the BCL6-mediated transcriptional landscape in human T cells, and next aims to elcudiate molecular mechanisms of action. Funding Sources This work was funded by grants from the US National Institutes of Health (NIH) P01AI145815 to S.C and from the South Korean Ministry of Science and ICT (MSIT) RS-2024-00333829 to DS.K. Topic Categories Immune Response Regulation: Molecular Mechanisms (IRM)