Contributions of PD-L1 reverse signaling to dendritic cell trafficking.

Programmed Death-1 (PD-1)/Programmed Death-Ligand 1 (PD-L1) interactions are critical for dampening the immune response to both self and foreign antigens. The signaling of PD-L1 via its cytoplasmic domain, rather than through its interactions with PD-1 via the extracellular domain, has been termed PD-L1 reverse signaling. While this signaling is beneficial for cancer progression, little is understood about the consequences of PD-L1 reverse signaling in immune cells that express PD-L1 at steady state or in response to infection. Loss of PD-L1 during infection leads to unchecked T cell proliferation and increased autoimmune T cell responses. While the T cell intrinsic role of PD-1 for inhibiting T cell responses has been well explored, little to no effort has been directed at investigating the consequences of PD-L1 reverse signaling on the DCs interacting with PD-1+ T cells. We recently reported a defect in dendritic cell trafficking from the skin to the draining lymph node following immunization or infection in the absence of PD-L1. We demonstrated that a region within the cytoplasmic tail was responsible for the defect in dendritic cell trafficking. Here, we review the processes involved in dendritic cell trafficking and highlight what we know about PD-L1 expression, PD-L1 post-translational modifications, PD-L1 intracellular interactions and PD-L1 extracellular interactions.