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Programmed cell death protein 1

Programmed cell death protein 1 (PD-1), also known as CD279 and encoded by the PDCD1 gene located on chromosome 2q37.3 in humans, is a type I transmembrane glycoprotein belonging to the immunoglobulin superfamily that serves as a key immune checkpoint receptor.^[1] Expressed primarily on the surface of activated T cells, B cells, natural killer (NK) cells, and other immune cells, PD-1 negatively regulates immune responses by inhibiting T cell activation, proliferation, cytokine secretion, and cytotoxicity upon ligand binding, thereby promoting peripheral immune tolerance and preventing autoimmunity.^[2] Originally discovered in 1992 through studies on apoptotic T cell hybridomas, PD-1 was identified as a novel member of the immunoglobulin gene superfamily induced during programmed cell death, highlighting its role in apoptosis regulation.^[3] Structurally, PD-1 consists of an extracellular immunoglobulin variable-like (IgV) domain, a transmembrane region, and an intracellular tail containing an immunoreceptor tyrosine-based inhibitory motif (ITIM) and an immunoreceptor tyrosine-based switch motif (ITSM), which recruit phosphatases like SHP-1 and SHP-2 to transduce inhibitory signals.^[2] Its primary ligands are programmed cell death ligand 1 (PD-L1, also CD274) and PD-L2 (PDCD1LG2), which are upregulated on antigen-presenting cells, endothelial cells, and various tumor cells in response to inflammatory cytokines such as interferon-gamma.^[4] The interaction between PD-1 and its ligands dampens effector T cell functions, maintaining immune homeostasis but also enabling pathogens and tumors to evade immune surveillance by inducing T cell exhaustion in chronic infections and cancer microenvironments.^[2] In oncology, the PD-1/PD-L1 axis has emerged as a critical target for immunotherapy, with monoclonal antibodies such as nivolumab and pembrolizumab—FDA-approved since 2014—blocking this pathway to reinvigorate antitumor T cell responses and achieving durable remissions in malignancies including melanoma, non-small cell lung cancer, and Hodgkin lymphoma.^[2] Beyond cancer, PD-1 dysregulation contributes to autoimmune diseases like rheumatoid arthritis and systemic lupus erythematosus, where enhancement of its signaling is under investigation for therapeutic modulation.^[5] Ongoing research continues to explore PD-1's expression on non-T cells, such as regulatory T cells and myeloid-derived suppressor cells, and its interplay with other checkpoints like CTLA-4 to refine combination therapies.^[6]

Discovery and history

Initial identification

The programmed cell death protein 1 (PD-1) was first identified in 1992 by Yoshimasa Ishida, Yutaka Agata, and Tasuku Honjo at Kyoto University through subtractive cDNA hybridization screening. This approach targeted genes upregulated during apoptosis in two murine cell lines: the antigen-stimulated T-cell hybridoma 2B4.11 and the interleukin-3 (IL-3)-deprived pro-B cell line LyD9, both of which undergo programmed cell death under these conditions.^[3] The newly cloned gene was designated PD-1, an abbreviation for "programmed cell death 1," reflecting its strong and transient induction specifically during the early stages of apoptotic cell death in these models, distinguishing it from other apoptosis-related genes.^[3] Sequence analysis of the PD-1 cDNA revealed it encodes a 288-amino-acid protein predicted to form a type I transmembrane glycoprotein with a molecular weight of approximately 55 kDa upon glycosylation, featuring an extracellular immunoglobulin variable-like domain, a transmembrane region, and an intracellular tail with potential signaling motifs.^[3] Further insight into PD-1's function emerged in 1999 from experiments with PD-1 knockout mice generated by Tasuku Honjo's group, which spontaneously developed lupus-like autoimmune diseases characterized by glomerulonephritis, proliferative arthritis, and autoantibodies, thereby establishing PD-1's critical role in maintaining immune tolerance and preventing autoimmunity.^[7]

Key milestones and recognition

Following the initial identification of PD-1 in 1992 by Tasuku Honjo's group through subtractive hybridization in apoptotic T cells, subsequent research rapidly advanced understanding of its function and interactions.^[8] In 2000, Gordon J. Freeman and colleagues identified PD-L1 (also known as B7-H1 or CD274) as the first ligand for PD-1, demonstrating that its engagement inhibits T cell receptor-mediated lymphocyte proliferation and cytokine production in T-cell assays.^[9] This discovery positioned PD-1 within the CD28/B7 family of immune regulators. In 2001, Yvonne Latchman and colleagues reported PD-L2 (CD273) as a second ligand for PD-1, further confirming its inhibitory role on T cell activation through similar functional assays.^[10] These findings from 2000 to 2002 established PD-1's core mechanism as an immune checkpoint, suppressing T cell responses to maintain tolerance. The groundbreaking contributions to PD-1 and related checkpoint research were recognized with the 2018 Nobel Prize in Physiology or Medicine, awarded jointly to Tasuku Honjo and James P. Allison for their discoveries of cancer therapy by inhibition of negative immune regulation, including PD-1's role alongside CTLA-4.^[8] Therapeutic advancements culminated in the 2023 U.S. Food and Drug Administration (FDA) approval of toripalimab-tpzi (Loqtorzi), a PD-1 inhibitor, in combination with cisplatin and gemcitabine for first-line treatment of adults with metastatic or recurrent locally advanced nasopharyngeal carcinoma, and as monotherapy for previously treated cases.^[11] In 2025, a comparative genomic analysis by R. Kondo and colleagues revealed PD-1's evolutionary conservation across jawed vertebrates, including sharks and bony fishes, indicating its ancient origin in adaptive immunity and highlighting conserved structural features with ligands PD-L1 and PD-L2, as well as interacting phosphatases like SHP-2.^[12]

Structure and biochemistry

Gene and protein domains

The PDCD1 gene encodes programmed cell death protein 1 (PD-1), an immune checkpoint receptor, and is located on the long arm of human chromosome 2 at position 2q37.3. This gene spans approximately 9 kb and consists of five exons, with exon 1 encoding the signal peptide, exon 2 the IgV-like domain, exon 3 the stalk and transmembrane domain, exon 4 the initial cytoplasmic region, and exon 5 the remainder of the cytoplasmic tail.^[1]^[13] The mouse homolog, Pdcd1, maps to chromosome 1 and shares high sequence similarity, facilitating comparative studies in immunology. The human PD-1 precursor protein comprises 288 amino acids, processed into a mature form by cleavage of the N-terminal signal peptide spanning positions 1-25. The extracellular region features an immunoglobulin variable-like (IgV-like) domain from residues 26-150, which adopts a β-sheet structure typical of the immunoglobulin superfamily and serves as the primary site for ligand interaction. This is followed by a short transmembrane helix (residues 171-191) that anchors PD-1 in the plasma membrane and a cytoplasmic tail (residues 192-288) containing key signaling elements, including an immunoreceptor tyrosine-based inhibitory motif (ITIM; sequence VTYAEL at positions approximately 223-228) and an immunoreceptor tyrosine-based switch motif (ITSM; sequence TEYATIV at positions approximately 248-254). These motifs become tyrosine-phosphorylated upon receptor engagement, enabling recruitment of phosphatases like SHP-1 and SHP-2.^[14]^[15]^[16] PD-1 belongs to the CD28/CTLA-4 family of T-cell costimulatory and coinhibitory receptors, sharing structural homology in the extracellular IgV-like domain and overall membrane topology, though PD-1 lacks the covalent dimerization seen in some family members. Post-translational modifications further regulate PD-1 function: N-linked glycosylation occurs at asparagine 49 (Asn49) within the IgV-like domain, contributing to protein stability and ligand binding affinity, while the cytoplasmic tail harbors serine/threonine phosphorylation sites, such as serine 261, that modulate intracellular trafficking and dephosphorylation dynamics. Alternative splicing of PDCD1 produces isoforms, including a soluble form lacking the transmembrane domain and an exon 3-skipped variant that alters inhibitory signaling.^[17]^[18]^[19]^[20]^[21]

Expression patterns

Programmed cell death protein 1 (PD-1) is primarily expressed on activated immune cells, including CD4⁺ and CD8⁺ T cells, B cells, natural killer (NK) cells, natural killer T (NKT) cells, activated monocytes, macrophages, and dendritic cells (DCs).^[22] Under steady-state conditions, PD-1 expression remains low on naive or resting T cells and B cells, with basal levels detectable on only a small subset of peripheral T cells.^[23] However, it is rapidly upregulated following activation, particularly through T-cell receptor (TCR) or B-cell receptor (BCR) stimulation, often becoming detectable within 24 hours and persisting in response to ongoing antigenic signals.^[24] In terms of tissue distribution, PD-1 shows high expression in primary and secondary lymphoid organs, including the thymus, spleen, and lymph nodes, where it is associated with maturing and antigen-experienced lymphocytes in germinal centers and white pulp regions.^[22] Expression is inducible in non-lymphoid tissues during inflammation, such as at sites of chronic infection (e.g., liver in hepatitis C virus infection or lungs in tuberculosis) or within tumor microenvironments, reflecting recruitment of activated PD-1⁺ immune cells to these locales.^[24] Developmentally, PD-1 expression is regulated during T-cell maturation in the thymus, where it is largely absent from the earliest progenitor stages but appears at low levels (3–5% of total thymocytes) on double-negative (CD4⁻CD8⁻) subsets during TCRβ rearrangement and the transition to double-positive thymocytes.^[25] This thymic expression supports processes like positive selection, but PD-1 levels remain modest overall in the thymus compared to peripheral tissues.^[22] In mature peripheral lymphocytes, expression peaks upon antigen encounter and activation, enabling its role in modulating responses in secondary lymphoid organs and inflamed sites.^[24] In chronic settings like persistent infections or cancer, sustained high PD-1 expression on these mature cells contributes to T-cell exhaustion.^[24]

Ligands and interactions

Primary ligands

The primary ligands of programmed cell death protein 1 (PD-1) are PD-L1 (also known as CD274 or B7-H1) and PD-L2 (also known as PDCD1LG2 or B7-DC), both members of the B7 family of immune-regulatory proteins.^[26]^[27] PD-L1 is a type I transmembrane glycoprotein consisting of 290 amino acids, featuring an extracellular domain with immunoglobulin variable-like (IgV) and constant-like (IgC) regions, a transmembrane domain, and a short cytoplasmic tail.^[28] It is broadly expressed on antigen-presenting cells such as dendritic cells and monocytes, as well as on tumor cells and endothelial cells, where its upregulation is often induced by inflammatory cytokines like interferon-gamma.^[28]^[29] PD-L1 binds to PD-1 with a dissociation constant (Kd) of approximately 770 nM, reflecting moderate affinity that contributes to its role in modulating immune responses.^[30] In contrast, PD-L2 is a 273-amino acid type I transmembrane protein with a similar IgV-IgC extracellular architecture but more restricted expression, primarily on dendritic cells and macrophages, particularly upon activation by stimuli such as interleukin-4 or granulocyte-macrophage colony-stimulating factor.^[31]^[32] Despite its lower baseline expression compared to PD-L1, PD-L2 exhibits higher binding affinity to PD-1, with a Kd of about 140 nM, enabling more stable interactions under physiological conditions.^[30]^[33] Both PD-L1 and PD-L2 can exist in soluble forms, generated through alternative mRNA splicing that produces truncated variants lacking the transmembrane domain or via proteolytic shedding of the membrane-bound protein by matrix metalloproteinases, allowing these circulating ligands to potentially influence systemic immune regulation.^[34] No other major ligands for PD-1 have been identified, though minor interactions between PD-L1 and CD80 (B7-1) have been reported, which do not constitute primary binding partnerships.^[35]

Binding mechanisms

The binding of programmed cell death protein 1 (PD-1) to its ligands, primarily PD-L1 and PD-L2, occurs through the immunoglobulin variable-like (IgV) domains of both proteins, forming a 1:1 stoichiometric complex that mimics the variable fragment (Fv) structure of antibodies. The interaction interface is centered on the front β-sheets and loops of these domains, specifically the CC' and FG loops of PD-1's IgV domain, which engage the corresponding IgV-like domain of PD-L1 or PD-L2 via hydrophobic and polar contacts. Key residues at this interface include tyrosine 123 (Tyr123) in PD-1's FG loop, which forms π-π stacking interactions, and methionine 115 (Met115) in PD-L1, contributing to the hydrophobic core of the binding pocket. Crystallographic studies, such as those deposited in the Protein Data Bank (PDB) under codes 3BIK (2008, murine PD-1/human PD-L1) and 3BP5 (2008, murine PD-1/PD-L2), reveal that the PD-1/PD-L1 complex adopts a compact, two-domain architecture with extensive buried surface area (~900 Å²), promoting partial dimerization through strand-swapped conformations in the ligands. While the core complex is 1:1, membrane-bound configurations allow for 2:1 stoichiometries, where one ligand molecule can engage two PD-1 molecules in cis (on the same cell) or trans (across cells), enhancing avidity in physiological settings. The binding kinetics reflect moderate affinity, with association rates (k_on) on the order of 10^5 M^{-1} s^{-1} and dissociation rates (k_off) around 10^{-1} s^{-1} for human PD-1/PD-L1, yielding equilibrium dissociation constants (K_D) of approximately 0.3–8 μM depending on the experimental system; PD-L2 exhibits 3–4-fold higher affinity due to slower dissociation.^[36] Regulation of these interactions is influenced by post-translational modifications and environmental factors. N-linked glycosylation on PD-L1, particularly at sites near the binding interface (e.g., Asn192, Asn200), sterically modulates ligand accessibility, with deglycosylated forms showing reduced PD-1 binding efficiency and altered immunosuppressive activity. Additionally, the binding exhibits pH sensitivity, with enhanced affinity in the acidic tumor microenvironment (pH ~6.5), where protonation of histidine residues (e.g., His56 in PD-1) stabilizes the interface, potentially amplifying immune suppression in hypoxic tumors.

Physiological functions

Immune checkpoint role

Programmed cell death protein 1 (PD-1) functions as a key immune checkpoint by delivering inhibitory signals to activated T cells, thereby preventing excessive immune responses during antigen-specific interactions. Upon ligation with its ligands, PD-1 attenuates T-cell receptor signaling, which inhibits T-cell proliferation and reduces the production of pro-inflammatory cytokines such as interferon-gamma (IFN-γ) and interleukin-2 (IL-2).^[37] This regulatory mechanism ensures that T-cell activation remains proportional to the antigenic stimulus, limiting potential tissue damage from overzealous immune activity.^[38] In peripheral tissues, PD-1 promotes immune tolerance by suppressing the activity of autoreactive T cells that may escape central tolerance mechanisms. By upregulating cell cycle inhibitors like p27 and p15, PD-1 engagement halts the expansion of self-reactive T lymphocytes, thereby maintaining self-tolerance and preventing autoimmune reactions in non-lymphoid organs.^[39] This process is particularly evident in scenarios involving chronic antigen exposure, where PD-1 helps balance effector functions with regulatory controls.^[40] PD-1 also exerts regulatory effects on B cells, contributing to the suppression of humoral immunity. Expressed on B lymphocytes, PD-1 signaling inhibits B-cell expansion and impairs antibody class switching, particularly in response to T-independent antigens, which limits the generation of long-lived plasma cells and excessive immunoglobulin production.^[41] This B-cell intrinsic inhibition helps fine-tune antibody responses to avoid hyperactivation.^[42] In mucosal tissues, PD-1 maintains immune homeostasis by preventing overreactions to commensal microbiota. The PD-1 pathway fosters tolerance to harmless gut antigens, ensuring that regulatory T cells and effector responses remain balanced to support symbiotic relationships without triggering inflammation.^[43] Disruption of this checkpoint, such as through PD-1 blockade, can convert mucosal tolerance into pathogenic responses against commensals.^[44]

Signaling pathways

Upon ligation, PD-1's intracellular tail, featuring an immunoreceptor tyrosine-based inhibitory motif (ITIM) and an immunoreceptor tyrosine-based switch motif (ITSM), undergoes phosphorylation, enabling the recruitment of Src homology 2 (SH2) domain-containing phosphatases SHP-1 and SHP-2.^[45] These phosphatases bind primarily to the ITSM (tyrosine 248 in humans), with SHP-2 showing stronger affinity, and dephosphorylate key proximal T-cell receptor (TCR) signaling components, including the zeta chain of the CD3 complex (CD3ζ) and zeta-chain-associated protein kinase 70 (ZAP70).^[46]^[22] This dephosphorylation disrupts the initiation of downstream TCR signals, thereby dampening T-cell activation.^[47] The recruited SHP-1 and SHP-2 phosphatases inhibit critical pathways essential for T-cell proliferation and effector functions, particularly the phosphoinositide 3-kinase (PI3K)-Akt pathway and the Ras-mitogen-activated protein kinase (MAPK) pathway.30156-X) By dephosphorylating intermediaries, PD-1 signaling reduces Akt activation downstream of PI3K, which is triggered by TCR and CD28 costimulation, leading to diminished metabolic reprogramming and survival signals in T cells.30156-X) Similarly, inhibition of the Ras-MAPK pathway, likely via SHP-2-mediated suppression of Ras guanine nucleotide exchange, attenuates extracellular signal-regulated kinase (ERK) phosphorylation, further curtailing cytokine production and cell growth responses from TCR/CD28 engagement.30156-X)^[47] A simplified model of phosphatase recruitment and activity can be represented as:

\text{Phospho-PD-1} + \text{SHP-2} \rightarrow \text{Dephospho-PD-1} + \text{p-ZAP70 (dephosphorylated to ZAP70)}

This reaction illustrates the transient docking of SHP-2 to phosphorylated PD-1, enabling dephosphorylation of ZAP70 and other substrates, though in practice, SHP-2 acts catalytically on multiple targets.^[46] These inhibitory effects culminate in reduced interleukin-2 (IL-2) production by activated T cells, impairing autocrine proliferation signals even in the presence of CD28 costimulation.^[48] PD-1 engagement also induces cell cycle arrest at the G0/G1 phase by suppressing cyclin-dependent kinase activity and related progression factors.^[49] Additionally, it promotes BIM-mediated apoptosis through upregulation of the pro-apoptotic BH3-only protein BIM, enhancing mitochondrial outer membrane permeabilization and caspase activation in T cells.^[50]

Role in diseases

Cancer

In the tumor microenvironment (TME), PD-1 is upregulated on tumor-infiltrating lymphocytes (TILs), particularly CD8+ T cells, leading to their exhaustion and anergy, which impairs effective anti-tumor immunity.^[51] This upregulation is driven by chronic antigen exposure and immunosuppressive signals from tumor-repopulating cells, resulting in reduced T-cell proliferation, cytokine production, and cytotoxicity. Consequently, PD-1 engagement promotes a state of T-cell dysfunction that allows tumor progression by evading immune surveillance.^[52] Cancer cells often overexpress PD-L1, the primary ligand for PD-1, which is induced by interferon-gamma (IFN-γ) secreted from activated T cells in the TME.^[53] This overexpression correlates with poor clinical prognosis in various malignancies, including melanoma, non-small cell lung cancer (NSCLC), and renal cell carcinoma (RCC).^[54] For instance, elevated PD-L1 levels on tumor cells in NSCLC and RCC are associated with advanced disease stages and reduced overall survival.^[51]^[55] PD-1 signaling also contributes to the suppressive function of regulatory T cells (Tregs) within the TME, enhancing their ability to inhibit anti-tumor responses from effector T cells. PD-1-expressing Tregs accumulate in tumors and promote an immunosuppressive milieu by limiting CD8+ T-cell activation and infiltration.^[56] High PD-1 and PD-L1 expression serves as a prognostic biomarker, predicting response to immunotherapy in approximately 20-40% of patients across PD-1/PD-L1-positive cancers.^[57]^[58] Tumors with substantial PD-L1 expression on immune or tumor cells are more likely to benefit from checkpoint blockade, highlighting its utility in patient stratification.^[57]

Autoimmune disorders

PD-1 plays a critical protective role in maintaining immune tolerance and preventing autoimmunity by inhibiting the activation and proliferation of autoreactive T cells. In genetic models, deficiency of PD-1 leads to spontaneous autoimmune disorders in mice. For instance, PD-1 knockout mice on the C57BL/6 background develop a lupus-like syndrome characterized by the production of anti-DNA antibodies, immune complex deposition, and glomerulonephritis, while those on the Balb/c background exhibit autoimmune dilated cardiomyopathy.^[59] Additionally, PD-1-deficient mice are prone to inflammatory arthritis resembling rheumatoid arthritis, with joint inflammation driven by dysregulated T-cell responses.^[60] These phenotypes highlight PD-1's essential function in suppressing self-reactive immune responses. In humans, polymorphisms in the PDCD1 gene, which encodes PD-1, have been associated with increased susceptibility to several autoimmune diseases. Specific variants, such as those in the promoter region or intronic sequences, correlate with higher risk of systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and type 1 diabetes.^[61] For example, the PD-1.3 polymorphism (rs11568821) is linked to SLE in multiple populations, potentially by altering PD-1 expression levels on T cells and reducing inhibitory signaling.^[61] Similarly, associations with RA and type 1 diabetes involve variants that impair PD-1's regulatory capacity, leading to enhanced autoreactivity.^[62] The underlying mechanism of PD-1's protective role involves its inhibition of T-cell receptor signaling, which prevents the unchecked expansion of autoreactive T cells and subsequent inflammatory cascades. Loss of PD-1 function results in hyperproliferative T cells that produce excessive proinflammatory cytokines, such as IFN-γ and IL-17, potentially culminating in cytokine storms that exacerbate tissue damage in autoimmune settings.^[40] This dysregulation is evident in PD-1-deficient models where T follicular helper cells and effector T cells fail to be properly restrained, promoting autoantibody production and chronic inflammation.^[40] Therapeutically, the recognition of PD-1's anti-autoimmune function has spurred interest in developing PD-1 agonists to restore tolerance in autoimmune diseases. Unlike PD-1 inhibitors used in cancer, agonists aim to enhance PD-1 signaling to suppress overactive immune responses. Several candidates, including monoclonal antibodies like peresolimab, have shown promise in preclinical models and early clinical trials for conditions such as RA and SLE, with phase II and III studies ongoing to evaluate efficacy and safety.^[63] However, no PD-1 agonists have received regulatory approval for autoimmune indications as of 2025.^[63]

Infectious diseases

In chronic viral infections such as HIV, hepatitis C virus (HCV), and lymphocytic choriomeningitis virus (LCMV), PD-1 is upregulated on virus-specific CD8+ T cells, leading to T cell exhaustion characterized by reduced proliferation, cytokine production, and cytotoxicity, which impairs viral clearance. This exhaustion is driven by sustained PD-1 signaling, resulting in a progressive loss of effector functions and contributing to persistent infection. For instance, in HIV, PD-1 expression correlates with diminished memory CD8+ T cell responses in typical progressors, exacerbating viral persistence. In bacterial infections like tuberculosis caused by Mycobacterium tuberculosis, PD-1 engagement inhibits antigen-specific CD4+ T cell proliferation and interferon-γ production, promoting immune evasion and disease progression.^[64] PD-1 blockade in experimental models restores T cell effector functions and enhances macrophage phagocytosis, reducing bacterial replication and improving host control of infection.^[64] In parasitic infections such as malaria caused by Plasmodium species, elevated PD-1 expression on parasite-specific CD8+ T cells induces exhaustion, marked by decreased interferon-γ secretion and granzyme B expression, which limits protective immunity and sustains chronic parasitemia.^[65] This PD-1-mediated dysfunction exacerbates blood-stage infection severity, as evidenced by faster parasite clearance and sterile immunity in PD-1-deficient mice compared to wild-type controls.^[65] However, PD-1 also restrains excessive T cell activation, thereby mitigating immunopathology during acute phases.^[65] PD-1 exhibits a dual role across infection types: in acute infections, it tempers T cell expansion and apoptosis to limit inflammation and support memory formation, whereas in chronic settings, it enforces exhaustion that hinders pathogen resolution.^[66] For example, transient PD-1 signaling during acute LCMV infection optimizes CD8+ T cell recall responses without inducing dysfunction.^[66]

Neurodegenerative conditions

Programmed cell death protein 1 (PD-1) has emerged as a key regulator in neuroinflammatory processes underlying Alzheimer's disease (AD), primarily through its expression on microglia and infiltrating T cells within the central nervous system. In AD models, PD-1 signaling on microglia, stimulated by astrocytic PD-L1, enhances the uptake and clearance of amyloid-β (Aβ) peptides, thereby mitigating plaque accumulation and associated neuroinflammation. Similarly, PD-1 on T cells promotes interferon-γ (IFN-γ) production, which recruits peripheral monocytes to cross the blood-brain barrier and facilitate Aβ phagocytosis, demonstrating a protective role in early disease stages. These mechanisms highlight PD-1's contribution to immune-mediated debris removal in the brain parenchyma. However, the dual nature of PD-1 signaling becomes apparent in chronic AD contexts, where prolonged activation shifts toward detrimental effects. While initial PD-1 engagement supports Aβ clearance and limits excessive inflammation, sustained signaling fosters a pro-inflammatory microenvironment that exacerbates synaptic loss and neuronal dysfunction. Deletion of microglial PD-1 in mouse models compromises Aβ uptake while triggering heightened inflammatory responses, underscoring the balance required for neuroprotection. In human AD, elevated PD-1 expression on peripheral T cells and increased PD-L1 levels in cerebrospinal fluid correlate with disease severity, including tau hyperphosphorylation and cognitive decline, as observed in postmortem analyses and cohort studies.^[67]^[68] Research from the 2020s has further elucidated PD-1's therapeutic potential through blockade strategies in preclinical AD models. Administration of anti-PD-1 antibodies in amyloidogenic mice reduces Aβ plaque burden and tau pathology by enhancing microglial activation and monocyte recruitment, leading to improved spatial memory performance. In tauopathy models, PD-1 inhibition decreases glycogen synthase kinase-3β activity and tau hyperphosphorylation, attenuating cognitive impairments. Nonetheless, such interventions carry risks of autoimmunity, including potential encephalitis from unchecked immune activation, necessitating careful modulation to avoid exacerbating neuroinflammation.^[69]^[70]

Therapeutic targeting

Inhibitory antibodies

Inhibitory antibodies targeting programmed cell death protein 1 (PD-1) represent a cornerstone of cancer immunotherapy, functioning as monoclonal antibodies that disrupt the PD-1 signaling pathway to reinvigorate antitumor immune responses. These agents, primarily human or humanized immunoglobulin G4 (IgG4) subtypes, bind specifically to the extracellular domain of PD-1 on T cells, thereby preventing its interaction with ligands such as PD-L1 and PD-L2.^[71]^[72] Pembrolizumab (Keytruda) is a humanized IgG4 monoclonal antibody approved by the U.S. Food and Drug Administration (FDA) in September 2014 for the treatment of unresectable or metastatic melanoma in patients with disease progression following ipilimumab and, if BRAF V600 mutation-positive, a BRAF inhibitor.^[71]^[73] It exerts its therapeutic effect by binding to the extracellular domain of PD-1, thereby blocking the interaction with its ligands and restoring T-cell-mediated cytotoxicity against tumor cells.^[74] This approval marked pembrolizumab as the first PD-1 inhibitor to receive FDA authorization, based on phase I/II trial data demonstrating objective response rates of approximately 26% in ipilimumab-refractory melanoma patients.^[73] Nivolumab (Opdivo), a fully human IgG4 monoclonal antibody, received initial FDA approval in December 2014 for unresectable or metastatic melanoma and was subsequently expanded in March 2015 to include advanced non-small cell lung cancer (NSCLC) after platinum-based chemotherapy.^[75]^[76] Its pharmacokinetic profile includes a half-life of approximately 25 days, enabling dosing regimens of 240 mg every 2 weeks or 480 mg every 4 weeks via intravenous infusion.^[77]^[78] Like other PD-1 inhibitors, nivolumab prevents ligand binding to PD-1, thereby enhancing T-cell activation and proliferation in the tumor microenvironment.^[79] Cemiplimab (Libtayo), another human IgG4 monoclonal antibody, was approved by the FDA in September 2018 for metastatic or locally advanced cutaneous squamous cell carcinoma (CSCC) in patients ineligible for curative surgery or radiation.^[80] On October 8, 2025, the FDA approved cemiplimab for the adjuvant treatment of adults with high-risk CSCC at risk of recurrence after surgery and radiation, based on phase 3 C-POST trial data showing a 68% reduction in the risk of recurrence or death compared to placebo.^[81] It shares a similar mechanism with pembrolizumab and nivolumab, binding to PD-1 to inhibit ligand engagement and promote antitumor T-cell responses.^[82] Clinical trials supporting its initial approval reported objective response rates ranging from 41% to 47% in advanced CSCC, with durable responses observed in a majority of responders; broader data across solid tumors indicate response rates of 15-50% depending on tumor type and PD-L1 expression.^[83]^[82] The core mechanism of these inhibitory antibodies involves steric blockade of the PD-1/PD-L1 interaction, which normally suppresses T-cell receptor signaling and cytokine production, leading to T-cell exhaustion in the tumor setting. By alleviating this inhibition, the antibodies restore T-cell cytotoxicity and proliferation, enabling effective immune attack on cancer cells.^[72] However, this enhanced immune activation can result in immune-related adverse events (irAEs), such as dermatitis, colitis, pneumonitis, and endocrinopathies, occurring in 10-20% of patients as severe (grade 3-4) events, necessitating vigilant monitoring and management.^[84]^[85]

Emerging modulators and combinations

Beyond traditional monoclonal antibodies, small-molecule inhibitors targeting the PD-1/PD-L1 pathway offer potential advantages in oral administration and tissue penetration. Other candidates, such as INCB086550, an oral PD-L1 small-molecule inhibitor, are in ongoing phase 1/2 trials evaluating safety and efficacy in patients with advanced cancers, highlighting improved pharmacokinetics over biologics. These agents aim to disrupt PD-1 signaling without the infusion requirements of antibodies, though challenges in selectivity and duration of inhibition persist. Bispecific antibodies that simultaneously target PD-1 pathway components and other checkpoints are advancing as multifunctional modulators. KN046, a bispecific antibody against PD-L1 and CTLA-4, has shown favorable efficacy and manageable toxicity in phase 2 trials for metastatic non-small cell lung cancer (NSCLC), including combinations with chemotherapy that improved progression-free survival.^[86] Multiple clinical trials of KN046 are ongoing in NSCLC, small cell lung cancer (SCLC), and other solid tumors in China, the U.S., and Australia as of 2025.^[87] This approach enhances immune activation by blocking multiple inhibitory signals, potentially broadening response rates in checkpoint-resistant tumors. Combinatorial strategies integrating PD-1 inhibitors with other therapies have significantly improved outcomes in oncology. The combination of nivolumab (anti-PD-1) and ipilimumab (anti-CTLA-4) in advanced melanoma yields a 5-year overall survival rate of 52%, substantially higher than monotherapy options.^[88] Similarly, in NSCLC, pembrolizumab (anti-PD-1) plus platinum-based chemotherapy increases objective response rates to approximately 48% and extends progression-free survival compared to chemotherapy alone, establishing it as a standard first-line regimen.^[89] These synergies leverage complementary immune mechanisms, though increased immune-related adverse events necessitate careful patient selection. Applications of PD-1 modulation extend beyond cancer to autoimmune and infectious diseases. PD-1 agonists, such as S-4321, a bifunctional antibody agonizing PD-1 and FcγRIIb, are in phase 1 trials for autoimmune conditions like systemic lupus erythematosus (SLE), aiming to restore immune tolerance without broad immunosuppression. In infectious diseases, peptide-based PD-1 immunomodulators enhance vaccine efficacy by countering PD-1-mediated T-cell exhaustion, demonstrating improved adaptive immunity in preclinical models of viral infections.^[90] These developments underscore PD-1's versatile role in immune regulation across disease contexts.

Preclinical research

Animal models of infection

Animal models have been instrumental in elucidating the role of PD-1 in T-cell exhaustion during chronic infections, particularly through blockade or knockout strategies that enhance antiviral responses while revealing potential risks of immunopathology. In rhesus macaque models of simian immunodeficiency virus (SIV) infection, which closely mimic HIV pathogenesis in humans, PD-1 blockade during chronic infection reduces plasma viral load by approximately 1-2 logs in treated animals and restores proliferative capacity and cytokine production in exhausted CD8+ T cells.^[91]^[92] This intervention expands SIV-specific CD8+ T cells in blood and lymphoid tissues, leading to improved viral control and prolonged survival compared to untreated controls.^[91] However, the effects on viral load are often transient without combination therapies, highlighting PD-1's central role in maintaining exhaustion during lentiviral persistence.^[93] The lymphocytic choriomeningitis virus (LCMV) model in mice provides a foundational system for studying PD-1-mediated exhaustion in chronic viral infections, where persistent LCMV Clone 13 induces high PD-1 expression on CD8+ T cells, impairing their effector functions and allowing viral persistence. Anti-PD-1 or anti-PD-L1 therapy in this model reinvigorates exhausted CD8+ T cells, enhancing proliferation, cytokine secretion (e.g., IFN-γ, TNF-α), and granzyme B production, which collectively reduce viral titers in tissues like the spleen and liver.^[94] These findings demonstrate PD-1's dominance in exhaustion but also the potential for functional restoration, though full clearance often requires combination approaches. In tuberculosis (TB) models, PD-1 knockout (KO) mice infected with Mycobacterium tuberculosis exhibit increased bacterial burden in the lungs, with higher colony-forming units compared to wild-type mice, due to impaired CD4+ and CD8+ T-cell responses and reduced IFN-γ production. However, this leads to exacerbated lung pathology, including severe inflammation, neutrophil infiltration, and early mortality, underscoring PD-1's protective role in limiting immunopathology during bacterial persistence. PD-1 blockade in wild-type mice similarly exacerbates disease in primate models, increasing susceptibility and risking disseminated infection.^[95]^[96] Translational limitations arise from species-specific differences in PD-1/PD-L1 interactions; human PD-1 binds its ligands with higher affinity and inhibitory potency than murine PD-1, potentially leading to overestimation of blockade efficacy in mouse models and challenges in primate translation. These variations affect T-cell suppression thresholds and must be considered when extrapolating preclinical findings to human infectious diseases. Recent 2025 studies confirm human PD-1's stronger inhibitory signaling compared to rodent orthologs.^[97]

Models of autoimmunity and transplantation

Studies in PD-1 knockout (KO) mice have been instrumental in demonstrating the protein's role in maintaining immune tolerance and preventing autoimmunity. These mice spontaneously develop a range of autoimmune disorders, including lupus-like glomerulonephritis, destructive arthritis, and dilated cardiomyopathy, with symptoms typically emerging by 6 months of age and progressing to multi-organ infiltration involving the heart, lungs, liver, and other tissues by 6-12 months, often leading to fatal outcomes.^[98]^[99] The autoimmune phenotype in PD-1 KO mice arises from dysregulated T cell activation and proliferation, highlighting PD-1's suppressive function on autoreactive lymphocytes. Notably, low-dose IL-2 therapy has been shown to ameliorate aspects of this autoimmunity by compensating for metabolic shifts in T cells and enhancing regulatory T cell function, thereby rescuing the mice from severe disease manifestations.^[100] In transplantation models, PD-1 signaling promotes allograft tolerance and survival, while its blockade exacerbates rejection. In murine heart transplant models with fully MHC-mismatched allografts, administration of anti-PD-1 antibodies or PD-1/PD-L1 pathway blockade accelerates acute rejection by enhancing alloimmune responses, particularly in costimulation-deficient settings where CD28 or B7 pathways are blocked.^[101] Similarly, in liver transplantation models, PD-1 blockade or deficiency in donor tissue leads to rapid acute rejection, underscoring the pathway's role in mitigating T cell-mediated damage to the graft.^[102] Conversely, strategies to enhance PD-1 signaling, such as T cell-specific overexpression of PD-1, prolong allograft survival in cardiac transplant models by fostering tolerance through ICOS-dependent mechanisms and reducing effector T cell responses.^[103] PD-1 agonists or mimetics have also been explored to extend survival in various allograft models, supporting their potential to induce long-term tolerance without broad immunosuppression.^[104] The collagen-induced arthritis (CIA) model in mice further illustrates PD-1's protective role against autoimmune joint inflammation. PD-1 KO mice exhibit exacerbated disease severity in CIA, characterized by increased joint swelling, higher arthritis scores, and enhanced Th17 cell differentiation, confirming PD-1's suppression of pathogenic T cell responses.^[105] Treatment with anti-PD-1 antibodies in wild-type CIA mice worsens inflammation, promotes proinflammatory cytokine production (e.g., IFN-γ and IL-17), and accelerates joint pathology, reinforcing that PD-1 blockade unleashes autoreactive CD4+ and CD8+ T cells.^[106] These findings support PD-1's function in limiting osteoclastogenesis and bone erosion in rheumatoid arthritis-like conditions. Insights from these preclinical models have directly informed the development of PD-1 agonists for therapeutic applications in autoimmunity and transplantation. In rheumatoid arthritis (RA), phase II clinical trials of the PD-1 agonist peresolimab have demonstrated disease improvement in patients with active RA, with reductions in disease activity scores and no major safety concerns.^[107] For transplantation, these animal studies guide efforts toward PD-1-enhancing agents to achieve immunosuppression without increasing infection risk, with ongoing preclinical work exploring agonist antibodies and fusion proteins to promote graft tolerance in clinical settings.^[104]

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