PD-L1-PD-1 interactions limit effector regulatory T cell populations at homeostasis and during infection

Phenotypic and transcriptional profiling of regulatory T (T_reg) cells at homeostasis reveals that T cell receptor activation promotes T_reg cells with an effector phenotype (eT_reg) characterized by the production of interleukin-10 and expression of the inhibitory receptor PD-1. At homeostasis, blockade of the PD-1 pathway results in enhanced eT_reg cell activity, whereas during infection with Toxoplasma gondii, early interferon-γ upregulates myeloid cell expression of PD-L1 associated with reduced T_reg cell populations. In infected mice, blockade of PD-L1, complete deletion of PD-1 or lineage-specific deletion of PD-1 in T_reg cells prevents loss of eT_reg cells. These interventions resulted in a reduced ratio of pathogen-specific effector T cells: eT_reg cells and increased levels of interleukin-10 that mitigated the development of immunopathology, but which could compromise parasite control. Thus, eT_reg cell expression of PD-1 acts as a sensor to rapidly tune the pool of eT_reg cells at homeostasis and during inflammatory processes.