Contributions of PD-L1 reverse signaling to dendritic cell trafficking
1Division of Gastroenterology and Hepatology, Department of Medicine, University of Colorado School of Medicine Aurora, CO, USA.
Insights
Programmed death-ligand 1 (PD-L1) reverse signaling impacts dendritic cell (DC) trafficking. Loss of PD-L1 impairs DC movement, affecting immune responses during infection and immunization.
Area of Science:
- Immunology
- Cell Biology
Background:
- Programmed death-1 (PD-1) and programmed death-ligand 1 (PD-L1) interactions regulate immune responses.
- PD-L1 reverse signaling, independent of PD-1, influences cancer but its role in immune cells is unclear.
- Loss of PD-L1 during infection can cause excessive T-cell activation and autoimmunity.
Purpose of the Study:
- Investigate the consequences of PD-L1 reverse signaling on dendritic cells (DCs).
- Explore the role of PD-L1 in DC trafficking from skin to lymph nodes.
- Understand PD-L1's intracellular and extracellular interactions in the context of immune cell function.
Main Methods:
- Review of existing literature on DC trafficking, PD-L1 expression, and interactions.
- Analysis of PD-L1's cytoplasmic tail region's role in DC function.
- Examination of PD-L1 post-translational modifications and intracellular interactions.
Main Results:
- PD-L1 deficiency causes defects in dendritic cell (DC) trafficking from skin to draining lymph nodes.
- A specific region within the PD-L1 cytoplasmic tail is crucial for normal DC trafficking.
- PD-L1's role extends beyond T-cell inhibition to regulating DC migration.
Conclusions:
- PD-L1 reverse signaling is critical for proper dendritic cell migration.
- Understanding PD-L1's multifaceted roles is essential for modulating immune responses.
- Further research into PD-L1 interactions can inform therapeutic strategies for infections and autoimmune diseases.
Abstract:
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 (DC) trafficking from the skin to the draining lymph node (LN) 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 DC trafficking. Here, we review the processes involved in DC trafficking and highlight what we know about PD-L1 expression, PD-L1 post-translational modifications, PD-L1 intracellular interactions, and PD-L1 extracellular interactions.
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