T follicular regulatory (Tfr) cells: Dissecting the complexity of Tfr-cell compartments

Germinal centers (GC) have been known as key anatomic structures in humoral immunity, where isotype switching and affinity maturation occur. As a consequence, elucidation of GC regulation has potential implications for the understanding of autoantibody-mediated diseases. It is now accepted that different regulatory mechanisms coexist, including the action of a specialized population of Foxp3⁺ regulatory T cells with unique access to the B-cell follicle: the T follicular regulatory (Tfr) cells. Tfr cells develop through a multistep process requiring migration through different compartments of lymphoid tissues. This review discusses the ontogeny and physiology of Tfr cells, their distribution within distinct anatomic compartments, and their function. A greater understanding of Tfr biology and GC regulation is likely to lead to better stratification of patients with autoantibody-mediated diseases, and to the identification of novel therapeutic targets.