TFH cells in bystander and cognate interactions with B cells

Follicular T‐helper (T_FH) cells play a crucial role in three aspects of the germinal center (GC) response. They promote GC formation, arbitrate competition among GC B cells to determine the outcome of affinity maturation, and regulate GC output of memory and plasma cells to shape the long‐lived humoral immune memory. Of fundamental importance are dynamic physical interactions between T_FH and B cells, which are the main platform for T_FH cells to deliver “help” factors to B cells and also for reciprocal signaling from B cells to maintain the helper state of T_FH cells. Recent work has significantly expanded our understanding of how T‐B interactions are spatiotemporally regulated and molecularly orchestrated to fulfill those T_FH functions. In this review, we elaborate two modes of T‐B interactions, the antigen‐specific or cognate mode in which T_FH cells engage individual antigen‐presenting B cells and the antigen nonspecific bystander mode in which T_FH cells are engaged with the ensemble of follicular B cells. We discuss findings that indicate how short‐lived cognate T‐B contacts coupled with an intercellular positive feedback drive affinity‐based selection and how bystander interactions between T and B cells regulate follicular T‐cell recruitment and maintenance of an appropriate helper state. We argue that this combination of bystander and cognate interactions with B cells constantly shapes the internal state of T_FH cells and provides the platform to execute their helper functions.