IL2 production predicts Tfh differentiation

Abstract

Abstract Naïve CD4 T cells differentiate into functionally distinct subsets in response to a set of extrinsic and intrinsic cues. Effector subsets, including Th1, Th2 and Th17 CD4s, are required for optimal cellular responses to invading pathogens, while class switched antibody responses depend on the differentiation of T follicular helper cells (Tfh). Development of both Tfh and non-Tfh occurs in parallel and involves two distinct but functionally related expression bifurcations. Upon formation of T cell receptor (TCR)/major histocompatibility (MHC) synapses with antigen-presenting cells (APC), a discrete subset of activated T cells secretes the cytokine IL2. Similarly, a portion of activated cells express the transcription factor Bcl6 and differentiate into Tfh cells, while the remainder express Blimp1 and develop into effector CD4s. However, the cellular, temporal and mechanistic relationships between these two bifurcations remain unclear. Here we show that the IL2 and Bcl6/Blimp1 expression bifurcations occur simultaneously, precede cell division, predict differentiation into Tfh and non-Tfh subsets, and are mechanistically related to antigen availability TCR density.