TFH cells in bystander and cognate interactions with B cells

Abstract

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.

Keywords: ICOS; ICOSL; PD-1; PD-L1; adhesion; follicular helper T cells; germinal center; immunological synapse; intravital imaging.