The body’s immune system maintains a delicate balance, identifying and eliminating threats while avoiding attacks on healthy tissues. This control relies on “immune checkpoints,” molecules that regulate immune cell activity. These checkpoints ensure immune responses are appropriate and do not become overactive. One such protein is Programmed Death-Ligand 2, or PDL2. This article explores PDL2’s role in the immune system.
Understanding PDL2
PDL2 is a protein that acts as a ligand for the Programmed Death-1 (PD-1) receptor. It is located on the surface of certain immune cells, particularly antigen-presenting cells like dendritic cells, macrophages, mast cells, and B cells.
PDL2’s binding partner is the PD-1 receptor, found on T cells, which are central to adaptive immunity. While PDL2 shares similarity with PD-L1, another PD-1 ligand, its expression is more restricted to specific cell types.
How PDL2 Regulates Immune Responses
PDL2 functions as an immune checkpoint, preventing excessive immune activation and protecting the body’s own tissues. When PDL2 on an antigen-presenting cell binds to the PD-1 receptor on a T cell, it delivers an inhibitory signal. This interaction applies a “brake” to the immune system.
This inhibitory signal dampens T-cell activity. By reducing T-cell proliferation and cytokine production, the PDL2-PD-1 pathway helps maintain peripheral tolerance, preventing the immune system from mistakenly attacking healthy self-tissues. T-cell activation leads to PDL2 upregulation, which then helps temper the immune response.
PDL2’s Impact on Cancer and Autoimmune Conditions
Dysregulation of PDL2’s function can contribute to various diseases. In cancer, tumor cells can express PDL2, enabling them to evade immune detection and destruction. This occurs because PDL2 on cancer cells binds to PD-1 on T cells, effectively “turning off” the anti-tumor immune response.
In autoimmune diseases, a compromised PDL2-PD-1 pathway can lead to the immune system attacking healthy tissues. An imbalance can result in uncontrolled immune responses against the body’s own cells. While PD-L1 is more widely targeted in current immunotherapies due to its broader expression, PDL2 still holds clinical relevance. PDL2 expression has been observed in the absence of PD-L1 in some tumor types and predicts response to anti-PD-1 therapy in head and neck squamous cell carcinoma.
Research and Therapeutic Approaches Involving PDL2
Research continues to explore PDL2’s role in disease and its potential as a therapeutic target. While the PD-1/PD-L1 pathway has transformed cancer treatment, PDL2 remains an active area of study. Scientists are investigating PDL2’s potential as a biomarker for predicting disease prognosis or a patient’s response to therapy in certain cancers or autoimmune conditions.
Studies show PDL2 expression can predict a worse prognosis in lower-grade gliomas and correlates with immune infiltration in the tumor microenvironment. Research also explores modulating PDL2 activity. This could involve enhancing immune responses against cancer by blocking PDL2, or dampening immune responses in autoimmune disorders. Although direct PDL2-specific drugs are less common than PD-L1/PD-1 inhibitors, dual blockade targeting both PD-L1 and PDL2 is being investigated for a more comprehensive approach to reactivating T cell function, particularly in cancers with high PDL2 expression like non-small cell lung cancer, head and neck cancers, and Hodgkin lymphoma.