PD-1 Receptor: Key Role in T Cell Regulation

The immune system must balance eliminating threats while avoiding excessive activation that could harm the body. One mechanism that helps maintain this balance is programmed cell death protein 1 (PD-1), a receptor on T cells that regulates immune responses.

Understanding PD-1’s function provides insight into its role in immune regulation and its relevance in diseases such as cancer and autoimmunity.

Structural Features of PD1

PD-1 is a type I transmembrane protein in the immunoglobulin superfamily. It consists of an extracellular immunoglobulin V-like domain, a transmembrane region, and an intracellular tail with two key signaling motifs. The extracellular domain binds ligands, while the intracellular region mediates downstream signaling. PD-1’s structure is highly conserved across species, underscoring its functional importance.

The extracellular domain adopts a β-sandwich structure, characteristic of immunoglobulin superfamily proteins. This domain interacts with its ligands, PD-L1 and PD-L2, through a binding interface involving specific amino acid residues. X-ray crystallography studies reveal that PD-1 engages its ligands through a relatively shallow binding groove, allowing for dynamic yet specific interactions. Mutational analyses highlight residues such as Glu136 and Arg113 as critical for ligand recognition.

The transmembrane region anchors PD-1 in the plasma membrane, ensuring structural stability and receptor localization. While it does not directly participate in ligand binding, it facilitates receptor clustering within lipid rafts, which assemble signaling complexes. Mutations in this region can alter PD-1 function, affecting its ability to modulate downstream pathways.

The intracellular domain contains two conserved signaling motifs: the immunoreceptor tyrosine-based inhibitory motif (ITIM) and the immunoreceptor tyrosine-based switch motif (ITSM). These motifs serve as docking sites for phosphatases such as SHP-2, which mediate PD-1’s inhibitory effects. Phosphorylation of tyrosine residues within these motifs is required for SHP-2 recruitment and signal transduction. The ITSM is indispensable for PD-1 function, as mutations in this motif abrogate signaling.

Expression Patterns

PD-1 expression is tightly regulated and varies based on T cell activation, differentiation, and tissue localization. Under homeostatic conditions, PD-1 is minimally expressed on naïve T cells but upregulated upon antigen stimulation. This induction occurs within hours of T cell receptor (TCR) engagement and is reinforced by co-stimulatory signals, particularly CD28. In acute responses, PD-1 expression is transient, whereas chronic antigen exposure leads to sustained expression.

Effector T cells exhibit a temporary increase in PD-1 levels before returning to baseline once the antigen is cleared. In contrast, chronic infections like hepatitis B virus (HBV) and human immunodeficiency virus (HIV) lead to sustained PD-1 expression, often associated with functional exhaustion. Blocking PD-1 in these contexts can partially restore T cell function.

Tissue-specific factors also influence PD-1 expression. Lymphoid organs, where antigen presentation is most active, serve as primary sites of PD-1 induction. Non-lymphoid tissues, including the liver, lung, and tumor microenvironments, sustain PD-1 expression due to continuous antigen exposure and inflammatory cytokines such as IL-10 and TGF-β.

Beyond T cells, PD-1 is expressed on B cells and natural killer (NK) cells, though at lower levels. In B cells, PD-1 is observed in germinal center reactions, influencing antibody affinity maturation. NK cells in chronic infections or tumor settings can also upregulate PD-1, which has been linked to diminished cytotoxic function. These findings suggest PD-1 plays a broader role in immune modulation beyond T cells.

Binding Interactions with PDL1 and PDL2

PD-1 interacts with its ligands, PD-L1 and PD-L2, through structural complementarity and affinity differences that influence binding dynamics. PD-L1, encoded by the CD274 gene, is broadly expressed across hematopoietic and non-hematopoietic cells, while PD-L2, encoded by PDCD1LG2, is primarily found on antigen-presenting cells. Despite sharing a conserved immunoglobulin-like domain, PD-L1 and PD-L2 differ in their extracellular regions, affecting binding strength and regulatory mechanisms.

Crystallographic studies show PD-1 engages PD-L1 through hydrophobic and electrostatic interactions that stabilize the complex. Key residues such as Ile134 and Tyr68 on PD-1 form critical contacts with PD-L1’s IgV domain, creating a micromolar-range binding affinity. This interaction has a slow dissociation rate, ensuring sustained engagement. In contrast, PD-1’s interaction with PD-L2 involves a slightly altered binding surface, leading to a higher affinity due to additional hydrogen bonding and a more extensive contact area.

Glycosylation further modulates PD-1 ligand interactions, particularly for PD-L1. Post-translational modifications, such as N-linked glycosylation at Asn192, influence structural conformation and binding efficiency. Glycosylated PD-L1 exhibits enhanced stability and reduced degradation, contributing to its widespread expression.

Role in T Cell Regulation

PD-1 acts as a modulatory checkpoint, fine-tuning T cell activity to prevent excessive stimulation while allowing appropriate immune engagement. Upon TCR activation, PD-1 counters co-stimulatory signals, suppressing intracellular pathways that drive T cell proliferation and effector function. This inhibition occurs through SHP-2 phosphatase recruitment, which dephosphorylates key signaling intermediates, dampening activation thresholds. Consequently, T cells exhibit reduced cytokine secretion and diminished proliferative capacity, particularly in chronic antigen exposure.

PD-1 helps maintain homeostasis within lymphoid organs, limiting unnecessary T cell expansion and preventing aberrant inflammatory responses. PD-1-deficient mice develop spontaneous lymphoproliferative disorders, illustrating its role in curbing unregulated T cell growth. Additionally, regulatory T cells (Tregs) rely on PD-1 signaling to sustain suppressive function. The balance between PD-1 expression and antigenic stimulation strength determines the extent of inhibition, reinforcing its role as a dynamic modulator rather than a binary off-switch.

Molecular Signaling Through PD1

PD-1’s inhibitory effects are mediated through intracellular signaling that modulates TCR pathways. Upon ligand binding, PD-1 undergoes phosphorylation at two tyrosine residues within its cytoplasmic tail, specifically in the ITIM and ITSM motifs. These phosphorylation events create docking sites for SHP-2, which dephosphorylates molecules such as CD3ζ and ZAP-70, reducing activation of the PI3K-Akt and MAPK pathways. This suppression limits cell proliferation, cytokine production, and survival signals, curbing T cell effector function.

Beyond direct TCR inhibition, PD-1 interferes with co-stimulatory pathways by modulating CD28 signaling. SHP-2 recruitment leads to dephosphorylation of PI3K-associated intermediates, reducing Akt activation and metabolic processes necessary for sustained immune responses. This shift decreases glucose uptake and glycolysis while promoting fatty acid oxidation, a hallmark of anergy or exhaustion in chronically stimulated T cells. The extent of suppression depends on TCR engagement strength and ligand availability, making PD-1 a modulator rather than an absolute inhibitor of T cell activity.

Association with Immune Dysregulation

Dysregulated PD-1 signaling is linked to various pathological conditions. In autoimmune disorders, reduced PD-1 function leads to unchecked T cell activation and tissue damage. In systemic lupus erythematosus (SLE), defective PD-1 signaling correlates with hyperactive autoreactive T cells, exacerbating inflammation. Similarly, rheumatoid arthritis patients exhibit lower PD-1 expression on synovial T cells, contributing to persistent joint inflammation. Genetic polymorphisms in PDCD1 are associated with increased autoimmune susceptibility, highlighting PD-1’s role in immune tolerance.

Conversely, excessive PD-1 signaling contributes to immune exhaustion in chronic infections and cancer. Persistent antigen exposure in HIV and hepatitis C virus (HCV) leads to sustained PD-1 upregulation, impairing T cell function. In tumors, cancer cells exploit PD-1 by expressing high PD-L1 levels, dampening anti-tumor immunity. PD-1 checkpoint inhibitors such as pembrolizumab and nivolumab have revolutionized cancer therapy by restoring T cell function. Clinical trials show significant survival improvements in melanoma and non-small cell lung cancer patients following PD-1 blockade. However, immune-related adverse effects, including colitis and pneumonitis, highlight the delicate balance required in targeting this pathway.