Regulatory mechanisms that control T-follicular helper and T-helper 1 cell flexibility

Following antigenic stimulation, CD4(+) T cells have the potential to differentiate into a number of specialized effector cell subtypes. To date, much progress has been made in defining the basic molecular mechanisms that regulate initial helper T-cell differentiation decisions. Emerging research in the field is now uncovering more complexity in the series of events that control helper T-cell commitment decisions than was previously appreciated. During the commitment process, helper T cells need to integrate both signals derived from the T-cell receptor and from the surrounding microenvironment. These external signals are then translated into internal changes in gene expression potential to ultimately define the functional characteristics of the cell. In this review, this topic will be discussed from the perspective of T-follicular helper (Tfh) and T-helper type 1 (Th1) cell differentiation. The focus will be on examining how the cytokine environment is perceived by signaling through signal transducer and activator of transcription (STAT) family proteins to initiate fate choices. The activities of STAT proteins are then in turn translated into changes in the molecular balance between B-cell lymphoma 6 (Bcl-6) and T-box expressed in T cells (T-bet), the helper T-cell lineage-specifying transcription factors that regulate Tfh and Th1 effector cell differentiation, respectively. Collectively, the knowledge of the molecular pathways that regulate Tfh and Th1 commitment have provided insight into the relationship between these two specialized helper T-cell subtypes and the potential for flexibility in their gene programs.