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

Abstract

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

Excessive immunosuppression by regulatory T cells antagonizes T cell response to schistosome infection in PD-1-deficient mice

“…japonicum infection, although the number of eggs was reduced significantly in PD-1-deficient mice and the granuloma size per egg concordantly increased. It is worth mentioning that in an infection model using Toxoplasma gondii , blockade of PD-L1, germline deletion of PD-1, or PD-1 deficiency in Tregs resulted in reduced pathogen-specific CD4 + T cell responses during infection [ 16 ]. Such discrepancies between different infection models suggest that the consequence of PD-1 deficiency is pathogen-dependent, revealing the complexity of modulating T cell responses via PD-1 to treat schistosomiasis.…”

“…Such results are in line with findings from cancer immunotherapies in which PD-1 blockade results in increased Treg suppression [ 14 ], which needs further verification as some studies reported opposite results that PD-1 blockade could help overcome Treg suppression [ 15 ]. Surprisingly another recent study showed that decreased antigen specific T cell response in Toxoplasma gondii infected mice which had germline deletion of PD-1 or Treg specific ablation of PD-1, was associated with increased parasite burden [ 16 ]. In a previous study, PD-1 blockade in mice were found to exacerbate liver pathology and enhance Th2 differentiation [ 17 ], however the consequence of PD-1 inhibition for pathogens or the T cell response in the liver were not elucidated.…”

Single-cell level temporal profiling of tumour-reactive T cells under immune checkpoint blockade

“…PD-1 expression is induced in T cells by persistent antigenic stimulation, and thus is related to T-cell "exhaustion" in chronic infections and cancer 7 8 . Blockade of the PD-1 axis by either anti-PD-1 or anti-PD-L1 can inhibit PD-1 binding to PD-L1 and thereby abrogate inhibitory PD-1 signalling 9 , in addition, the PD-1 signalling pathway may inhibit Treg activities 10,11 . Thus, simultaneous blockade of CTLA-4 and PD-1 has been shown to induce robust antitumour T cell responses 12 , through expanding activated effector CD8 + T cells 13 14 , and a reduction in Treg-mediated immune-suppression 15 .…”

PD-1 and CTLA-4 exert additive control of effector regulatory T cells

“…Consequently, there need to be mechanisms to balance T reg cell activities such as IL-2 availability as a mechanism involved in modulation of the T reg cell pool 25,26 . In addition, there is evidence that the inhibitory receptors PD-1 27,28 and CTLA-4 21 restrict T reg cell activities in the setting of cancer, autoimmunity and infection 21,22,28 .…”

“…In addition, the ability of the extracellular domain of CTLA-4 to sequester CD80/86 provides an additional trans mechanism to limit accessory cell function required for optimal effector T cell activities 32 . A subset of T reg cells also express these receptors 22,28 , and several reports have highlighted that effector (eT reg ) cells express the highest levels of PD-1 and CTLA-4 27,28 . It appears that eT reg cells receive continuous TCR signals, but constitutive signals through PD-1 constrain the size of the eT reg cell pool 27,28 .…”