Signals that drive T follicular helper cell formation

T follicular helper (Tfh) cells are a distinct type of CD4⁺ T cell specialized in providing help to B cells during the germinal centre (GC) reaction. As such, they are critical determinants of the quality of an antibody response following antigen challenge. Excessive production of Tfh cells can result in autoimmunity whereas too few can result in inadequate protection from infection. Hence, their differentiation and maintenance must be tightly regulated to ensure appropriate but limited help to B cells. Unlike the majority of other CD4⁺ T-cell subsets, Tfh cell differentiation occurs in three phases defined by their anatomical location. During each phase of differentiation the emerging Tfh cells express distinct patterns of co-receptors, which work together with the T-cell receptor (TCR) to drive Tfh differentiation. These signals provided by both TCR and co-receptors during Tfh differentiation alter proliferation, survival, metabolism, cytokine production and transcription factor expression. This review will discuss how engagement of TCR and co-receptors work together to shape the formation and function of Tfh cells.