The receptor PD-1 controls follicular regulatory T cells in the lymph nodes and blood

CD4(+)CXCR5(+)Foxp3(+) follicular regulatory T cells (T-FR cells) inhibit humoral immunity mediated by CD4(+)CXCR5(+)Foxp3(-) follicular helper T cells (T-FH cells). Although the inhibitory receptor PD-1 is expressed by both cell types, its role in the differentiation of T-FR cells is unknown. Here we found that mice deficient in PD-1 and its ligand PD-L1 had a greater abundance of T-FR cells in the lymph nodes and that those T-FR cells had enhanced suppressive ability. We also found substantial populations of T-FR cells in mouse blood and demonstrated that T-FR cells in the blood homed to lymph nodes and potently inhibited T-FH cells in vivo. T-FR cells in the blood required signaling via the costimulatory receptors CD28 and ICOS but were inhibited by PD-1 and PD-L1. Our findings demonstrate mechanisms by which the PD-1 pathway regulates antibody production and help reconcile inconsistencies surrounding the role of this pathway in humoral immunity.