Bcl-6 is the nexus transcription factor of T follicular helper cells via repressor-of-repressor circuits

T follicular helper (TFH) cells are a distinct type of CD4+T cells that are essential for most antibody and B lymphocyte responses. TFHcell regulation and dysregulation is involved in a range of diseases. Bcl-6 is the lineage-defining transcription factor of TFHcells and its activity is essential for TFHcell differentiation and function. However, how Bcl-6 controls TFHbiology has largely remained unclear, at least in part due to the intrinsic challenges of connecting repressors to gene upregulation in complex cell types with multiple possible differentiation fates. Multiple competing models were tested here by a series of experimental approaches to determine that Bcl-6 exhibits negative autoregulation and controls pleiotropic attributes of TFHdifferentiation and function, including migration, costimulation, inhibitory receptors and cytokines, via multiple repressor-of-repressor gene circuits.