INTRODUCTION: The immunoinhibitory ligands PD-L1 and PD-L2 belong to the B7 family of co-stimulatory molecules. PD-L1 and PD-L2 are important checkpoint molecules that act to limit T cell immunity. Cancer cells use increased expression of PD-L1 and PD-L2 to suppress anti-tumour immunity. While PD-L1 is expressed by both hematopoietic and non-hematopoietic cells, PD-L2 expression is more restricted to antigen presenting cells including dendritic cells.
METHODS: We have used the murine-derived dendritic cell line MuTu DC to study cell surface expression of PD-L1 and PD-L2 in dendritic cells under different stimulatory conditions. In addition, we have monitored the expression of PD-L1 and PD-L2 on murine cDC in settings of tumour adoptive T cell immunotherapy using a B-cell lymphoma model.
RESULTS: PD-L1 and PD-L2 show distinct expression on the surface of dendritic cells. First, basal levels of both ligands are low on resting dendritic cells, with PD-L1 exhibiting higher surface expression than PD-L2. Second, we tested changes in the expression of PD-L1 and PD-L2 following treatment of dendritic cells with stimuli including PMA/ionomycin, bacterial agonists (LPS, CpG) and inflammatory cytokines (IFNa, IFNg, IL-4, IL-2, IL-10). Expression of PD-L1 is significantly increased by all stimuli while in contrast, PD-L2 displays a more regulated pattern of expression. Preliminary data demonstrates that PD-L1/2 expression by dendritic cells and antigen-expressing lymphoma is regulated during tumour immunotherapy in response to the killing of tumour cells via transferred antigen-specific cytotoxic T lymphocyte.
CONCLUSION:In summary, resting and activated dendritic cells display differential and regulated expression of PD-L1 and PD-L2. The underlying molecular mechanisms will be investigated. Knowledge of how PD-L1 and PD-L2 are expressed has important consequences for understanding how these immunoinhibitory molecules act to limit T cell immunity in settings of infection and/or tumours.