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

Abstract

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 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 exhibited negative autoregulation and controlled pleiotropic attributes of T _FH differentiation and function, including migration, costimulation, inhibitory receptors, and cytokines, via multiple repressor-of-repressor gene circuits.