Inhibitory signals through the PD-1 pathway regulate T cell activation, T cell tolerance, and T cell exhaustion. Studies of PD-1 function have focused primarily on effector T cells. Far less is known about PD-1 function in regulatory T (T reg) cells. To study the role of PD-1 in T reg cells, we generated mice that selectively lack PD-1 in T reg cells. PD-1–deficient T reg cells exhibit an activated phenotype and enhanced immunosuppressive function. The in vivo significance of the potent suppressive capacity of PD-1–deficient T reg cells is illustrated by ameliorated experimental autoimmune encephalomyelitis (EAE) and protection from diabetes in nonobese diabetic (NOD) mice lacking PD-1 selectively in T reg cells. We identified reduced signaling through the PI3K–AKT pathway as a mechanism underlying the enhanced suppressive capacity of PD-1–deficient T reg cells. Our findings demonstrate that cell-intrinsic PD-1 restraint of T reg cells is a significant mechanism by which PD-1 inhibitory signals regulate T cell tolerance and autoimmunity.

Summary Defective antibody production in aging is broadly attributed to immunosenescence. However, the precise immunological mechanisms remain unclear. Here we demonstrate an increase in the ratio of inhibitory T follicular regulatory (Tfr) cells to stimulatory T follicular helper (Tfh) cells in aged mice. Aged Tfh and Tfr cells are phenotypically distinct from those in young mice, exhibiting increased PD-1 expression but decreased ICOS expression. Aged Tfh cells exhibit defective antigen-specific responses, and PD-L1 blockade can partially rescue Tfh cell function. In contrast, young and aged Tfr cells have similar suppressive capacity on a per cell basis in vitro and in vivo. Together these studies reveal mechanisms contributing to defective humoral immunity in aging: an increase in suppressive Tfr cells combined with impaired function of aged Tfh cells results in reduced T cell dependent antibody responses in aged mice.