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

T follicular helper (T-FH) cells are a distinct type of CD4(+)T cells that are essential for most antibody and B lymphocyte responses. T(FH)cell regulation and dysregulation is involved in a range of diseases. Bcl-6 is the lineage-defining transcription factor of T(FH)cells and its activity is essential for T(FH)cell differentiation and function. However, how Bcl-6 controls T(FH)biology 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 T(FH)differentiation and function, including migration, costimulation, inhibitory receptors and cytokines, via multiple repressor-of-repressor gene circuits. Bcl-6 is the signature transcription factor for T(FH)cells. Crotty and colleagues provide a comprehensive transcriptional map depicting the regulatory circuitry controlled by Bcl-6 in determining T(FH)cell fate and function.