Control of TFH cell numbers: why and how?

T follicular helper (TFH) cells are essential for formation of germinal centres (GCs) and selection of mutated GC B cells. It has become clear over the last decade that precise control of TFH cell numbers is important to produce optimally affinity-matured antibody responses that are devoid of self-reactivity. Indeed, limiting the number of TFH cells appears important to impose competition amongst B-cell clones and set a selection threshold that will favour survival of high affinity clones. In contrast, excessive number of TFH cells appears to lower the selection threshold and allow survival of low affinity or self-reactive clones. Here, we review the cell-intrinsic and cell-extrinsic mechanisms that influence TFH cell homeostasis, including recent insights into novel modes of regulation by T-cell costimulators, toxic metabolites, microRNAs, RNA-binding proteins and regulatory cells.