PDCD1 - programmed cell death 1 |Elisa - Clia - Antibody - Protein

Background

Programmed cell death 1 (PDCD1), commonly referred to as PD-1, is a transmembrane protein and immune checkpoint receptor expressed primarily on the surface of T cells, B cells, and some myeloid cells. PD-1 is encoded by the PDCD1 gene and plays a pivotal role in regulating immune responses by inhibiting T-cell activation, particularly in peripheral tissues during inflammation. It serves as a checkpoint receptor that, when engaged, dampens the immune response, promoting self-tolerance and preventing autoimmune reactions. PD-1 binds to its ligands, PD-L1 (CD274) and PD-L2 (PDCD1LG2), which are expressed on antigen-presenting cells (APCs) and various tissue cells, particularly in inflamed or tumor environments.

The PD-1 pathway is critical for maintaining immune homeostasis, particularly in contexts where a controlled immune response is necessary, such as in infection and inflammation, and in preventing autoimmunity. PD-1 is often upregulated in chronic infections and cancer, where it contributes to immune exhaustion by inhibiting the function of T cells that would otherwise target infected or malignant cells. Given its role, PD-1 and its ligands have become significant targets for immunotherapy, especially in oncology, where blocking the PD-1/PD-L1 interaction can reinvigorate anti-tumor immunity.

Protein Structure

PD-1 is a type I transmembrane glycoprotein composed of approximately 288 amino acids. The structure of PD-1 includes three main regions: the extracellular domain, the transmembrane domain, and the intracellular signaling domain.

Extracellular Domain:

• The extracellular domain contains an IgV-like domain, characteristic of the immunoglobulin (Ig) superfamily, which enables PD-1 to interact with its ligands, PD-L1 and PD-L2.
• This IgV-like domain forms a compact β-sheet structure with loops that create the binding interface for its ligands. The PD-1/PD-L1 interaction occurs via an extended surface area, allowing moderate binding affinity that is suitable for regulated immune interactions.
• This domain also contains N-linked glycosylation sites, which are critical for proper folding, ligand binding, and stability.

Transmembrane Domain:

• The transmembrane region is a hydrophobic α-helix that anchors PD-1 in the cell membrane. It stabilizes PD-1 on the cell surface, allowing it to remain accessible to interact with PD-L1 and PD-L2.
• This domain also plays a role in maintaining the spatial organization of PD-1 on T cells, which is important for efficient ligand binding in areas where APCs are present.

Intracellular Domain:

• The intracellular domain contains two signaling motifs: an immunoreceptor tyrosine-based inhibitory motif (ITIM) and an immunoreceptor tyrosine-based switch motif (ITSM).
• The ITIM and ITSM motifs are phosphorylated upon PD-1 engagement with its ligands, which recruits Src homology region 2 domain-containing phosphatase 2 (SHP-2). SHP-2 dephosphorylates signaling molecules downstream of the T cell receptor (TCR) or B cell receptor (BCR), effectively reducing T-cell activation and cytokine production.
• This inhibition pathway via SHP-2 is essential for the role of PD-1 in attenuating immune responses, as it reduces proliferation and effector functions of T cells, thus limiting excessive immune activation.

The structural configuration of PD-1 is essential for its role as an immune checkpoint, allowing it to interact effectively with ligands and mediate inhibitory signals that regulate immune function.

Classification and Subtypes

PD-1 is a member of the CD28/B7 superfamily of receptors, which includes costimulatory molecules such as CD28 and CTLA-4, as well as other inhibitory receptors like BTLA. Unlike CD28, which primarily provides positive costimulatory signals, PD-1 is an inhibitory receptor with unique signaling characteristics that set it apart from other family members. PD-1’s closest structural relatives are CTLA-4 and BTLA, but it differs from CTLA-4 in its ligands and specific mechanism of action. PD-1 has no distinct subtypes; however, its expression is inducible and regulated in response to T cell receptor signaling and cytokine exposure.

PD-1 is mainly expressed on T cells upon activation but is also found on B cells, natural killer (NK) cells, and myeloid cells in certain circumstances, indicating its broad role in immune regulation.

Function and Biological Significance

The primary function of PD-1 is to serve as an immune checkpoint that modulates T cell activity to prevent overactivation of the immune response and maintain tolerance to self-antigens. This function has several critical aspects:

Inhibition of T-cell Activation:

• PD-1 suppresses T cell proliferation, cytokine production, and cytotoxic activity, which prevents tissue damage during inflammation and infection. When PD-1 binds to PD-L1 or PD-L2, signaling pathways are activated that reduce T cell receptor (TCR) signaling strength and prevent full activation of the T cell.

Maintenance of Tolerance and Prevention of Autoimmunity:

• PD-1 signaling promotes peripheral tolerance by inhibiting autoreactive T cells that escape thymic deletion. This is essential in protecting against autoimmune diseases, where PD-1 helps control potentially pathogenic self-reactive cells in peripheral tissues.
• PD-1’s role in regulatory T cells (Tregs) enhances their suppressive function, adding an additional layer of immune tolerance regulation, particularly in peripheral tissues.

Role in Immune Exhaustion in Chronic Infections and Cancer:

• During chronic infections (e.g., HIV, hepatitis), PD-1 expression is upregulated on T cells, leading to T cell exhaustion, a state where T cells lose their effector functions. This exhaustion helps to prevent excessive tissue damage but can hinder viral clearance.
• In cancer, PD-1 is often upregulated in the tumor microenvironment, where it contributes to the immune evasion of cancer cells. By engaging with PD-L1 expressed on tumor cells or stromal cells, PD-1 signaling reduces T-cell mediated killing of tumor cells, allowing cancers to persist and grow.

Modulation of B cell Responses:

• Although PD-1’s primary role is in T cells, its expression on B cells suggests a role in regulating humoral immunity. PD-1 modulates B cell activation, survival, and differentiation, impacting antibody production. This is particularly relevant in chronic immune responses where PD-1 may limit excessive antibody production.

Clinical Issues

Given its central role in immune regulation, PD-1 has significant implications in both autoimmune diseases and cancer immunotherapy:

Autoimmune Diseases:

• Genetic polymorphisms in the PDCD1 gene have been associated with autoimmune diseases, including systemic lupus erythematosus (SLE), type 1 diabetes, and rheumatoid arthritis (RA). Reduced PD-1 function due to mutations or polymorphisms may lead to insufficient inhibition of autoreactive T cells, increasing the risk of autoimmune reactions.
• Therapies targeting PD-1 are being explored to potentially reduce autoimmunity by enhancing PD-1 pathway activity.

Cancer Immunotherapy:

• In oncology, PD-1 inhibitors are widely used as immunotherapy agents, with monoclonal antibodies like pembrolizumab, nivolumab, and cemiplimab targeting PD-1 to block its interaction with PD-L1/PD-L2.
• Blocking PD-1/PD-L1 interactions releases T cells from the inhibitory effects of PD-1, allowing them to attack cancer cells more effectively. This strategy has shown success in treating various cancers, including melanoma, non-small cell lung cancer, renal cell carcinoma, and others.
• However, the use of PD-1 inhibitors can lead to immune-related adverse events (irAEs) due to heightened immune activity, manifesting as inflammation in organs like the skin, gastrointestinal tract, and liver.

Chronic Infections:

• PD-1 expression is increased in T cells during chronic viral infections, leading to immune exhaustion. Therapies aimed at blocking PD-1 in these contexts are under investigation to restore immune function against persistent pathogens.
• Caution is necessary, as inhibiting PD-1 may lead to increased tissue damage due to an uncontrolled immune response, especially in cases of chronic hepatitis or other infections where tissue integrity is already compromised.

Summary

Programmed cell death 1 (PD-1) is a key immune checkpoint receptor expressed primarily on T cells and plays a critical role in modulating immune responses. Structurally, PD-1 is composed of an IgV-like extracellular domain, a transmembrane domain, and an intracellular domain with ITIM and ITSM motifs essential for its inhibitory signaling. Upon binding to its ligands PD-L1 and PD-L2, PD-1 recruits SHP-2 to downregulate TCR and BCR signaling, effectively reducing T cell activation.

PD-1’s primary function is to inhibit excessive immune responses, maintain immune tolerance, and prevent autoimmunity. It also contributes to immune exhaustion during chronic infections and cancer, where sustained PD-1 expression inhibits effective immune clearance. Clinically, PD-1 has become a prominent target for cancer immunotherapy, with PD-1 inhibitors proving effective in restoring anti-tumor immunity. However, its inhibition can lead to autoimmune side effects, underscoring its complex role in immune balance and disease.