Affinage

Showing PDCD1LG2 — PD-L2 is a alias.

PDCD1LG2

Programmed cell death 1 ligand 2 · UniProt Q9BQ51

Length
273 aa
Mass
31.0 kDa
Annotated
2026-06-10
100 papers in source corpus 35 papers cited in narrative 35 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PDCD1LG2 (PD-L2/B7-DC) is a cell-surface immunoglobulin-superfamily ligand that functions as a coinhibitory checkpoint on antigen-presenting cells, restraining T cell activation by engaging PD-1 (PMID:11224527, PMID:16864790). Through its IgV domain it binds PD-1 with roughly 3-fold higher affinity than PD-L1, a property conferred by a C-D β-strand 'latch' and a W110 'elbow' that respectively enhance affinity and limit engagement duration, and the two ligands compete for the same binding site on PD-1 (PMID:20587542, PMID:31882544, PMID:31727844). Engagement triggers PD-1 microcluster formation at the immunological synapse that recruits SHP-2 phosphatase, suppressing TCR-driven PI3K/AKT and ERK/MAPK signaling and arresting proliferation and cytokine production (PMID:16278812, PMID:33990697). Its expression is differentially controlled relative to PD-L1: it is induced by IL-4/STAT6 during alternative macrophage activation, by NF-κB, and equally by IFN-β and IFN-γ through direct promoter binding of IRF1 and STAT3 (PMID:12697896, PMID:14515254, PMID:28494868). In cancer, PD-L2 is co-regulated with PD-L1 by a shared super-enhancer organized within a TAD that recruits STAT3/IRF1 to drive synchronous transcription, is driven by oncogenic EGFR/ALK signaling, and is post-translationally stabilized by FUT8-mediated N-glycosylation that blocks lysosomal degradation and promotes EGFR complex formation (PMID:31825827, PMID:35530130, PMID:29596910, PMID:34697216); loss of these ligands restores T cell-mediated tumor killing (PMID:31825827, PMID:38267628). Beyond PD-1, PD-L2 binds a second receptor, RGMb, through which it costimulates Th1 responses, and blockade of the PD-L2-RGMb axis sensitizes PD-1/PD-L1-resistant tumors (PMID:28479601, PMID:37138075). PD-L2 also exerts cell-intrinsic, receptor-independent functions in tumor cells, promoting invasion and metastasis via RhoA-ROCK-LIMK2 and c-Src/FAK signaling and suppressing ferroptosis by acting as an RNA-binding protein that stabilizes FTL mRNA (PMID:30886151, PMID:39159723, PMID:39284838). On immune cells it sustains peripherally induced Treg numbers and function through metabolic regulation and limits B-1 cell natural antibody production via IL-5 suppression (PMID:36045140, PMID:28768724).

Mechanistic history

Synthesis pass · year-by-year structured walk · 18 steps
  1. 2001 High

    Established that PD-1 has a second ligand beyond PD-L1 and that this ligand delivers an inhibitory signal to T cells, defining PD-L2 as a coinhibitory checkpoint molecule.

    Evidence Cell-based binding and T cell proliferation/cytokine assays with Western blotting for SHP-2 phosphorylation

    PMID:11224527

    Open questions at the time
    • Did not resolve structural basis of PD-1 binding
    • Downstream signaling beyond SHP-2 recruitment not mapped
  2. 2003 Medium

    Defined PD-L2 as differentially regulated from PD-L1, induced by Th2/IL-4-STAT6 and NF-κB rather than the classical activation pathway, indicating context-specific deployment of the two ligands.

    Evidence Macrophage and dendritic cell stimulation in STAT6-/-, STAT1-/-, and NF-κB p50-/-p65+/- knockouts with flow cytometry

    PMID:12697896 PMID:14515254

    Open questions at the time
    • Promoter elements bound by these factors not mapped
    • Human regulation not directly tested
  3. 2003 Medium

    Provided early evidence for a PD-1-independent costimulatory function, hinting at a second receptor for PD-L2 long before its identification.

    Evidence Tumor rejection and cytotoxicity assays using PD-1-/- cells

    PMID:12810690

    Open questions at the time
    • Identity of the second receptor unknown at the time
    • Single-lab finding
  4. 2005 Medium

    Connected PD-L2/PD-1 engagement to specific intracellular cascades, showing rapid AKT and delayed ERK suppression downstream of SHP-2 activation in human T cells.

    Evidence Human T cell assays with phospho-AKT/ERK blotting, SHP-2 phosphatase activity, and PD-1 co-IP

    PMID:16278812

    Open questions at the time
    • Spatial organization of signaling not resolved
    • Single lab
  5. 2006 High

    Genetic knockout established that PD-L2 negatively regulates T cell activation and oral tolerance in a PD-1-dependent manner in vivo.

    Evidence PDL2-/- mice with in vitro/in vivo T cell activation and tolerance assays plus PD-1-dependence tests

    PMID:16864790

    Open questions at the time
    • Tissue-specific contributions not dissected
    • Did not address non-PD-1 receptor
  6. 2009 High

    Demonstrated that PD-L1 and PD-L2 can play opposing roles in tissue immunity, distinguishing PD-L2's function from PD-L1 in airway disease.

    Evidence Reciprocal PD-L1-/- and PD-L2-/- mouse asthma models with iNKT transfer and in vitro blockade

    PMID:19741598

    Open questions at the time
    • Molecular basis of opposing effects unresolved
    • Receptor mediating effect not defined
  7. 2010 High

    Resolved the binding kinetics relationship between PD-L1 and PD-L2 for PD-1, showing comparable affinity but distinct mechanisms and shared binding site.

    Evidence SPR, cell-surface binding, and competition assays with blocking mAbs

    PMID:20587542

    Open questions at the time
    • Structural determinants of kinetic differences not identified
    • Functional consequence of kinetic distinction untested
  8. 2017 Medium

    Identified RGMb as the long-sought second receptor for PD-L2 and showed it mediates PD-1-independent Th1 costimulation, explaining earlier PD-1-independent observations.

    Evidence K113S PD-1-binding-deficient PD-L2 mutant in binding and costimulation assays plus a murine asthma model

    PMID:28479601

    Open questions at the time
    • RGMb downstream signaling not mapped
    • Single lab
  9. 2017 High

    Established the dominant interferon-responsive transcriptional control of PD-L2 by IRF1 and STAT3, distinguishing it from the STAT1-centric regulation of PD-L1.

    Evidence siRNA knockdown of JAK/STAT/IRF components and ChIP at the PD-L2 promoter in melanoma cells

    PMID:28494868

    Open questions at the time
    • Did not address chromatin architecture
    • Cooperation with PD-L1 locus not yet shown
  10. 2019 High

    Defined the structural basis of PD-L2's affinity advantage, attributing the net 3-fold higher PD-1 affinity to a C-D latch and W110 elbow, and crystallized the human PD-1/PD-L2 complex.

    Evidence SPR with systematic mutagenesis, phylogenetic analysis, deep mutational scanning, and X-ray crystallography of the PD-1/PD-L2 complex

    PMID:31727844 PMID:31882544

    Open questions at the time
    • Functional consequence of the affinity advantage in vivo not quantified
    • Required a high-affinity PD-1 mutant for crystallization
  11. 2019 High

    Showed that PD-L1 and PD-L2 are coordinately driven by a shared super-enhancer organized into a TAD recruiting STAT3/IRF1, linking the transcriptional logic of both ligands.

    Evidence CRISPR deletion of PD-L1L2-SE, RNA-seq, ChIP-seq, Hi-C, and T cell killing assays

    PMID:31825827 PMID:35530130

    Open questions at the time
    • Upstream signals activating the super-enhancer not fully mapped
    • Generalizability across tumor types not established
  12. 2019 Medium

    Revealed tumor-cell-intrinsic, receptor-independent functions of PD-L2, driving invasion and metastasis through RhoA-ROCK-LIMK2 and autophagy regulation.

    Evidence PD-L2 knockdown in osteosarcoma lines with migration/invasion assays, pathway blotting, and orthotopic mouse model

    PMID:30886151

    Open questions at the time
    • How surface PD-L2 transduces an intracellular signal unclear
    • Single lab and tumor type
  13. 2018 Medium

    Identified oncogenic drivers (EGFR mutations, EML4-ALK) and the macrophage compartment as sources of PD-L2 that become functionally important when PD-L1 is blocked, rationalizing combination checkpoint blockade.

    Evidence Oncogene gain/loss-of-function in lung cells, TKI/siRNA, and antibody combination plus BM chimera tumor experiments

    PMID:29596910 PMID:30357491

    Open questions at the time
    • Relative contribution of tumor vs myeloid PD-L2 not quantified across cancers
    • Single lab per study
  14. 2021 High

    Defined the spatial signaling mechanism, showing PD-L2 nucleates PD-1/SHP2 coinhibitory microclusters that compete with PD-L1 at TCR microclusters.

    Evidence Super-resolution live-cell imaging of PD-1 microclusters with SHP2 co-localization, competition, and mAb inhibition

    PMID:33990697

    Open questions at the time
    • Quantitative threshold for inhibition not defined
    • Single lab
  15. 2021 High

    Established post-translational control of PD-L2 by FUT8-mediated N-glycosylation that stabilizes the protein, links it to EGFR signaling, and promotes immune evasion.

    Evidence Co-IP, glycosylation-site mutagenesis, FUT8 knockdown, ubiquitination and cytotoxicity assays, and in vivo tumor model

    PMID:34697216

    Open questions at the time
    • Glycan structures not fully characterized
    • Single lab
  16. 2022 High

    Revealed an immune-intrinsic role for PD-L2 in sustaining peripheral Treg numbers and function through epigenetic and metabolic regulation of Foxp3 stability.

    Evidence PD-L2-/- mice with iTreg generation, TSDR methylation, mitochondrial metabolic assays, and DC transfer/pyruvate rescue

    PMID:36045140

    Open questions at the time
    • Direct link between PD-1 signaling and Treg metabolism mechanistically incomplete
    • Human relevance not tested
  17. 2023 High

    Showed the gut microbiome modulates the PD-L2-RGMb axis and that blocking it overcomes resistance to PD-1/PD-L1 therapy, establishing therapeutic relevance of the second-receptor pathway.

    Evidence Antibody blockade in germ-free/antibiotic/colonized tumor models, conditional T cell RGMb deletion, and fecal transplant

    PMID:37138075

    Open questions at the time
    • Microbial species and metabolites responsible not fully defined
    • RGMb downstream signaling incomplete
  18. 2024 Medium

    Expanded PD-L2's intrinsic repertoire by showing it acts as an RNA-binding protein to stabilize FTL mRNA and suppress ferroptosis, and by linking it to senescence-associated immune evasion and exosomal/c-Src-FAK invasion programs.

    Evidence SMYD3/H3K4me3 ChIP and ferroptosis assays, FTL mRNA stability assays, proteomics-based senescence screen with KO tumor models, exosome characterization, and PD-L2/c-Src Co-IP

    PMID:38267628 PMID:39159723 PMID:39284838 PMID:39511147

    Open questions at the time
    • RNA-binding mechanism of a surface ligand structurally unexplained
    • Findings are single-lab and tumor-type specific

Open questions

Synthesis pass · forward-looking unresolved questions
  • How a cell-surface ligand executes its diverse cell-intrinsic functions (RNA binding, cytoskeletal/invasion signaling) and how these reconcile with its canonical surface coinhibitory role remains unresolved.
  • No unified model linking surface ligand and intracellular functions
  • Topology enabling intracellular RNA binding unexplained
  • RGMb downstream signaling cascade undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005198 structural molecule activity 3 GO:0048018 receptor ligand activity 3 GO:0003723 RNA binding 1
Localization
GO:0005886 plasma membrane 3 GO:0031410 cytoplasmic vesicle 1
Pathway
R-HSA-162582 Signal Transduction 3 R-HSA-168256 Immune System 3 R-HSA-74160 Gene expression (Transcription) 3 R-HSA-392499 Metabolism of proteins 1
Partners
C-SRCEGFRFTLFUT8PDCD1RGMBSHP2

Evidence

Reading pass · 35 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2001 PD-L2 was identified as a second ligand for PD-1 that inhibits T cell activation: engagement of PD-1 by PD-L2 dramatically inhibits TCR-mediated proliferation and cytokine production by CD4+ T cells, leads to cell cycle arrest in G0/G1, and ligation of PD-1 + TCR leads to rapid phosphorylation of SHP-2. Cell-based binding assays, T cell proliferation and cytokine assays, Western blotting for SHP-2 phosphorylation Nature immunology High 11224527
2003 PD-L2 expression depends on IL-4Rα and STAT6 signaling, whereas PD-L1 expression depends on TLR4 and STAT1, demonstrating that PD-L1 and PD-L2 are differentially regulated by Th1 and Th2 signals on macrophages; PD-L2 is induced by IL-4 (alternative activation) but not by LPS/IFN-γ (classical activation). Macrophage stimulation assays, STAT6-/- and STAT1-/- knockout cells, flow cytometry for surface expression Proceedings of the National Academy of Sciences of the United States of America High 12697896
2003 PD-L2 (B7-DC) can promote CD8 T cell-mediated tumor rejection via a PD-1-independent mechanism: B7-DC binds to PD-1-/- cells and enhances T cell killing, indicating a second receptor/pathway for B7-DC costimulation. Tumor rejection assays in PD-1-/- mice, T cell cytotoxicity assays, binding studies on PD-1-deficient cells The Journal of experimental medicine Medium 12810690
2003 PD-L2 transcription is regulated through NF-κB (p50/p65): PD-L2 expression was dramatically reduced in NF-κB p50-/-p65+/- dendritic cells, whereas PD-L1 was not similarly affected, demonstrating distinct transcriptional regulation of the two ligands. Genetic knockout (NF-κB p50-/-p65+/- mice), dendritic cell expression assays European journal of immunology Medium 14515254
2005 PD-L2 inhibits human T cell proliferation, IL-2 and IFN-γ production via PD-1; this inhibition involves suppression of PI3K/AKT and ERK/MAPK pathways (PD-L2 inhibits anti-CD3-induced AKT phosphorylation within minutes and ERK phosphorylation after hours), and is accompanied by increased SHP-2 phosphatase activity associated with PD-1. Human T cell activation assays, phospho-AKT and phospho-ERK Western blotting, SHP-2 phosphatase activity assays, co-immunoprecipitation of SHP-2 with PD-1 European journal of immunology Medium 16278812
2006 PDL2 negatively regulates T cell activation and tolerance via PD-1: antigen-presenting cells from PDL2-/- mice were more potent in activating T cells in a PD-1-dependent manner; PDL2-/- mice showed increased CD4+ and CD8+ T cell activation in vivo and abrogated oral tolerance. PDL2 knockout mouse generation, in vitro T cell activation assays with APCs, in vivo immunization and tolerance induction, PD-1-dependent rescue experiments Proceedings of the National Academy of Sciences of the United States of America High 16864790
2006 PD-1/PD-L1, but not PD-1/PD-L2, interactions are crucial for attenuating T cell responses in experimental autoimmune encephalomyelitis (EAE): PD-L2-/- mice did not develop more severe EAE, unlike PD-1-/- and PD-L1-/- mice which showed elevated IFN-γ, TNF, IL-6, and IL-17. PD-L2-/- mouse immunization for EAE induction, cytokine measurement by ELISA, disease severity scoring Journal of neuroimmunology Medium 17182110
2009 PD-L2 on lung dendritic cells plays an inhibitory role on iNKT cell activation: PD-L2-/- mice showed greater airway hyperreactivity and higher IL-4 production by iNKT cells; blocking PD-L2 in vitro enhanced IL-4 production. PD-L2 expression on lung DCs is upregulated by allergen and IL-4. In contrast, PD-L1 deficiency reduced AHR, demonstrating opposing roles for the two ligands. PD-L2-/- and PD-L1-/- mouse models, allergen and α-GalCer challenge, iNKT cell transfer experiments, in vitro PD-L2 blockade, cytokine measurement Mucosal immunology High 19741598
2010 PD-L1 and PD-L2 bind PD-1 with comparable overall affinities but with distinct kinetic mechanisms: PD-L1 shows a delayed interaction consistent with conformational transition, while PD-L2 does not; PD-L1 and PD-L2 compete for the same PD-1 binding site. Surface plasmon resonance (SPR), cell surface binding assays, competition experiments with blocking mAbs International immunology High 20587542
2011 PD-L2 is expressed on activated human CD4+ and CD8+ T cells (not only on APCs), and PD-L2 engagement at the surface of T cells downregulates cytokine production and cell proliferation, indicating a bidirectional regulatory role. Flow cytometry for PD-L2 surface expression on T cell subsets, functional assays with PD-L2 engagement on T cells Molecular immunology Medium 21752471
2012 PD-L2 promotes airway hyperresponsiveness via a PD-1-independent mechanism by inhibiting dendritic cell IL-12 production: PD-L2 blockade reduced allergen-induced AHR and enhanced serum IL-12, while PD-1 blockade had no effect; in vitro, PD-L2-Fc stimulation of DCs reduced IL-12 p70 production. PD-L2 blockade in murine asthma model, PD-1 blockade comparison, in vitro DC stimulation with PD-L2-Fc, IL-12 ELISA Mucosal immunology Medium 23149662
2017 PD-L2 expression is primarily regulated by both IRF1 and STAT3 in response to interferons: IRF1 and STAT3 bind to the PD-L2 promoter; PD-L2 responds equally to interferon-beta and interferon-gamma, unlike PD-L1 which is primarily regulated by the IFN-γ-JAK1/JAK2-STAT1/STAT2/STAT3-IRF1 axis. siRNA knockdown of signaling components (JAK1, JAK2, STAT1, STAT2, STAT3, IRF1), chromatin immunoprecipitation (ChIP) for IRF1 and STAT3 at PD-L2 promoter, interferon stimulation of melanoma cells Cell reports High 28494868
2017 PD-L2 (B7-DC) binds RGMb (repulsive guidance molecule b) as a second receptor distinct from PD-1; a PD-1-binding-deficient PD-L2 mutant (K113S) retains binding to RGMb with similar affinity to wild-type and can costimulate CD4+ T cell Th1 responses via RGMb, promoting Th1 polarization and suppressing Th2-mediated asthma. PD-L2 K113S mutant protein binding assays, recombinant protein co-stimulation assays, RGMb expression analysis on immune cells, murine asthma model Cellular & molecular immunology Medium 28479601
2019 PD-L2 has a higher affinity for PD-1 (approximately 3-fold) than PD-L1, attributable to two structural features that evolved in placental mammals: a C-D β-strand 'latch' that enhances affinity and a W110 'elbow' that acts to reduce engagement duration; these two opposing features combine to give the net 3-fold affinity advantage of PD-L2. Surface plasmon resonance (SPR) with recombinant proteins, mutational analysis of W110 and C-D region, phylogenetic analysis The Journal of biological chemistry High 31882544
2019 Binding of PD-L2 to human PD-1 induces formation of a prominent pocket in the CC' and FG loop regions of PD-1 via substantial conformational changes; a triple-mutant high-affinity PD-1 variant (two orders of magnitude higher affinity for PD-L2) enabled crystallization of the human PD-1/PD-L2 complex, revealing the structural basis of the interaction. Deep mutational scanning, yeast surface display selection, X-ray crystallography of human PD-1/PD-L2 complex at 2.0 Å and apo PD-1 at 1.2 Å Proceedings of the National Academy of Sciences of the United States of America High 31727844
2019 PD-L2 promotes osteosarcoma invasion and metastasis via tumor cell-intrinsic signaling through the RhoA-ROCK-LIMK2 pathway; PD-L2 knockdown suppresses migration and invasion, inhibits EMT, and reduces autophagy by decreasing beclin-1 expression; beclin-1 in turn regulates RhoA-ROCK-LIMK2 activity. PD-L2 siRNA knockdown in osteosarcoma cell lines, wound-healing and transwell assays, Western blotting for RhoA-ROCK-LIMK2, EMT markers and beclin-1, orthotopic nude mouse model Cell death & disease Medium 30886151
2019 A super-enhancer (PD-L1L2-SE) located between the CD274 and CD273 genes drives synchronous co-expression of both PD-L1 and PD-L2 in cancer cells; genetic deletion of PD-L1L2-SE profoundly reduces expression of both ligands and abolishes immune evasion, rendering cells sensitive to T cell-mediated killing. Super-enhancer inhibitor treatment, CRISPR-based genetic deletion of PD-L1L2-SE, RNA-seq, ChIP-seq, T cell killing assays Cell reports High 31825827
2019 PD-L1L2 super-enhancer region (chr9:5,400,000-5,600,000) forms a topologically associating domain (TAD) around CD274 and CD273 that allows transcription factors STAT3 and IRF1 to be recruited to the PD-L1 locus to drive synchronous transcription of PD-L1 and PD-L2. Hi-C chromatin conformation analysis, ChIP-seq for STAT3 and IRF1, super-enhancer mapping Acta pharmaceutica Sinica. B Medium 35530130
2019 PD-L2 expressed on tumor cells in the presence of PD-L1 suppresses tumor antigen-specific CD8+ T cell responses; PD-L2-only tumors confer resistance to anti-PD-L1 mAb that can be overcome by anti-PD-1 mAb or combined anti-PD-L2 mAb; PD-L2 is upregulated on tumor-associated macrophages when mice are treated with anti-PD-L1 mAb. Syngeneic mouse tumor models with PD-L1/PD-L2 combination knockouts, antibody treatments, flow cytometry for tumor-infiltrating lymphocytes and TAM phenotyping Clinical cancer research Medium 31076547
2018 PD-L2 expression on tumor-associated macrophages (TAMs) becomes functionally relevant for immune suppression specifically when PD-L1 is blocked; anti-PD-L2 mAb treatment showed profound synergy with anti-PD-L1 mAb in anti-tumor responses, whereas anti-PD-L2 mAb alone had minimal effect; bone marrow chimera experiments showed that hematopoietic cell-derived PD-L1 (from BM-derived cells) also contributes to immune suppression. Anti-PD-L2/PD-L1 mAb treatment in tumor models, bone marrow chimeric mice, flow cytometry for TAM phenotyping Cancer immunology, immunotherapy Medium 30357491
2018 PD-L2 expression in non-small cell lung cancer is induced intrinsically by activating EGFR mutations and EML4-ALK fusion oncoproteins (suppressed by corresponding TKIs or siRNA knockdown), and extrinsically by IFN-γ via STAT1 signaling; STAT3 and c-FOS transcription factors contribute to both intrinsic and extrinsic pathways of PD-L2 induction. Stable expression of activated EGFR/EML4-ALK mutants in BEAS-2B cells, TKI treatment, siRNA knockdown of EGFR/ALK/STAT3/c-FOS, IFN-γ stimulation, RT-PCR and flow cytometry Journal of thoracic oncology Medium 29596910
2020 GATA2 is sufficient to drive constitutive PD-L2 (and PD-L1) expression in brain tumor cells and is necessary specifically for PD-L2 expression; GATA2 acts through cis-regulatory regions in the PDCD1LG2 locus; PD-L2 overexpression inhibits neoantigen-specific T cell IFN-γ production. Luciferase reporter assays with PDCD1LG2 cis-regulatory regions and GATA2 binding site mutations/deletions, flow cytometry for PD-L2 protein, IFN-γ ELISPOT for T cell function Scientific reports Medium 32493985
2021 PD-L2 undergoes N-glycosylation by FUT8 (fucosyltransferase), a transcriptional target of STAT3; glycosylated PD-L2 forms a complex with EGFR, activating EGFR/STAT3 signaling and reducing cetuximab binding affinity to EGFR; glycosylation stabilizes PD-L2 by blocking ubiquitin-dependent lysosomal degradation and promotes PD-L2 binding to PD-1 and immune evasion. Co-immunoprecipitation of PD-L2 with EGFR, N-glycosylation site mutagenesis, FUT8 knockdown, ubiquitination assays, STAT3 inhibitor treatment, in vitro T cell cytotoxicity, in vivo tumor model Journal for immunotherapy of cancer High 34697216
2021 PD-L2 suppresses T cell signaling by forming coinhibitory microclusters ('PD-1 microclusters') with SHP2 phosphatase at the immunological synapse; PD-L2 competes with PD-L1 for the same PD-1 binding space at TCR microclusters; PD-1 microcluster formation (visible by imaging) is inhibited by specific mAbs. High-resolution live-cell imaging (super-resolution microscopy), PD-1/PD-L2 microcluster visualization, SHP2 co-localization analysis, competition experiments with PD-L1, mAb functional inhibition assays Communications biology High 33990697
2022 PD-L2 controls peripherally induced regulatory T (pTreg) cell numbers and function via PD-1/PD-L2 interactions: PD-L2 deficiency reduces splenic pTreg numbers, decreases IL-10 production, impairs suppressive activity, lowers Foxp3 expression, increases TSDR methylation, and disrupts mitochondrial TCA cycle/ATP production in pTregs; PD-L2high DC transfer restores pTreg numbers in PD-L2KO mice. PD-L2-/- mouse model, in vitro iTreg generation, TSDR methylation analysis, mitochondrial metabolic assays (TCA cycle, ATP), adoptive transfer of PD-L2high DCs, pyruvate rescue experiments Nature communications High 36045140
2023 The gut microbiome downregulates PD-L2 expression and its binding partner RGMb to promote anti-tumor immunity; antibody-mediated blockade of the PD-L2-RGMb pathway (separate from PD-1) combined with anti-PD-1 or anti-PD-L1 promotes anti-tumor responses in multiple tumor models resistant to PD-1/PD-L1 blockade alone, including germ-free and antibiotic-treated mice. PD-L2 and RGMb antibody blockade in germ-free/antibiotic-treated/conventionally colonized mouse tumor models, conditional RGMb deletion in T cells, fecal transplant experiments, gene expression analysis Nature High 37138075
2024 PD-L2 is upregulated upon induction of cellular senescence in cancer cells (identified by unbiased proteomics); PD-L2 is required for senescent cancer cells to evade immune clearance—PD-L2-deficient senescent cells are rapidly eliminated; PD-L2-deficient pancreatic tumors fail to recruit myeloid-derived suppressor cells and undergo CD8 T cell-driven regression after chemotherapy. Proteomics screen, PD-L2 knockout in cancer cell lines, murine tumor models with chemotherapy, flow cytometry for immune cell infiltrates (MDSC, CD8 T cells), senescence assays Nature cancer High 38267628
2017 PD-L2 regulates B-1 cell natural antibody production against phosphorylcholine (PC) via an IL-5-dependent mechanism: B-1 cell-intrinsic PD-L2 expression inhibits IL-5 production by T cells, which in turn limits B-1 cell plasmablast differentiation and PC-specific IgM production; PD-L2 mAb blockade increased IL-5+ T cells and CD138/Blimp1 expression on B-1 cells. PD-L2-/- mice and irradiated chimeras reconstituted with PD-L2-/- B cells, in vitro B-1 cell culture with PD-L2 mAb blockade, IL-5 neutralization and STAT5 inhibition, flow cytometry, ELISA Journal of immunology Medium 28768724
2010 PD-L2 induction on dendritic cells by Mycobacterium avium is mediated through the TLR2-p38 MAPK signaling pathway and requires IL-10 production; M. avium-exposed DCs with PD-L2 expression impair activation of BCG-specific T cells through PD-1:PD-L interactions. Bone marrow-derived DC stimulation with M. avium, TLR2 knockdown, p38 MAPK inhibition, IL-10 neutralization, flow cytometry for PD-L2, antigen-specific T cell activation assays Tuberculosis (Edinburgh, Scotland) Medium 21147037
2024 PD-L2 is predominantly expressed on the surface of exosomes derived from clear cell renal cell carcinoma (ccRCC) cells; tumor-derived exosomal PD-L2 (TDE-PD-L2) suppresses T cell function in a PD-1-dependent manner, increasing regulatory T cells and decreasing cytotoxic CD8+ T cells both in tumor-infiltrating and splenic compartments; anti-PD-L2 antibody restores immune function. Exosome isolation and characterization, flow cytometry for surface PD-L2 on exosomes, in vitro T cell co-culture assays, in vivo tumor models with immune-competent vs immunodeficient mice, antibody blockade Cell death & disease Medium 39511147
2021 In gastric cancer, tumor cell-derived G-CSF induces FasL and PD-L2 expression on neutrophils via the JAK-STAT3 signaling pathway, while Th17 cell-derived IL-17A induces FasL and PD-L2 via ERK-NF-κB signaling; FasL+ PD-L2+ neutrophils acquire immunosuppressive functions that suppress tumor-specific CD8+ T cells in a manner reversible by blocking FasL and PD-L2. Cytokine stimulation of neutrophils, JAK/STAT3 and ERK/NF-κB inhibitor assays, flow cytometry for FasL and PD-L2, co-culture with CD8+ T cells, in vivo tumor growth assays Advanced science Medium 34957697
2024 Matrix stiffness-induced PD-L2 suppresses ferroptosis in hepatocellular carcinoma: SMYD3 (a histone methyltransferase) activated by matrix stiffening drives H3K4me3-mediated transcriptional induction of PD-L2, which then acts as an RNA-binding protein to enhance mRNA stability of FTL (ferritin light chain), elevating FTL protein and inhibiting xCT (SLC7A11)-mediated ferroptosis. SMYD3 knockdown/overexpression, H3K4me3 ChIP, PD-L2 knockdown on stiff substrates, ferroptosis assays (cell viability, ferrous iron, mitochondrial pathology), FTL mRNA stability assays, in vivo tumor model Journal of advanced research Medium 39159723
2024 SPHK1/S1P signaling promotes PD-L2 expression in bladder cancer via Akt/β-catenin activation; PD-L2 then interacts with c-Src (co-immunoprecipitation confirmed), which further activates FAK, promoting cancer cell invasion and migration. CRISPR/Cas9 SPHK1 KO and constitutive activation, PD-L2 knockdown/overexpression, co-immunoprecipitation of PD-L2 with c-Src, FAK phosphorylation assays, invasion/migration assays, in vivo tumor model Cell death & disease Medium 39284838
2019 EBV microRNA BHRF1-2-5p binds to the 3'UTR of PD-L2 (and PD-L1) mRNA to reduce their surface protein expression, acting as a counterregulatory mechanism to fine-tune LMP1-driven amplification of PD-L2 expression in EBV+ DLBCL. 3'UTR reporter assays, EBV-infected B cell differentiation model, EBV miR BHRF1-2-5p overexpression/inhibition, flow cytometry for surface PD-L2 Blood Medium 31856276
2019 Topical siRNA silencing of PD-L2 in cutaneous dendritic cells inhibits elicitation of contact hypersensitivity by suppressing early pro-inflammatory cytokine expression and migration of hapten-carrying DCs to lymph nodes; this effect is independent of PD-1/PD-L1 but dependent on local memory T cells, suggesting PD-L2 acts as a costimulator in this context. Topical siRNA application, anti-PD-L2 mAb injection, CHS assay in PD-1/PD-L1 double KO mice, T cell transfer experiments, cytokine measurement The Journal of investigative dermatology Medium 30978356

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2001 PD-L2 is a second ligand for PD-1 and inhibits T cell activation. Nature immunology 2352 11224527
2017 Interferon Receptor Signaling Pathways Regulating PD-L1 and PD-L2 Expression. Cell reports 1477 28494868
2016 PD-L1 and PD-L2 Genetic Alterations Define Classical Hodgkin Lymphoma and Predict Outcome. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 653 27069084
2013 Expression of PD-L1, PD-L2, PD-1 and CTLA4 in myelodysplastic syndromes is enhanced by treatment with hypomethylating agents. Leukemia 591 24270737
2003 Regulation of PD-1, PD-L1, and PD-L2 expression during normal and autoimmune responses. European journal of immunology 532 14515254
2003 PD-L1 and PD-L2 are differentially regulated by Th1 and Th2 cells. Proceedings of the National Academy of Sciences of the United States of America 522 12697896
2017 PD-L2 Expression in Human Tumors: Relevance to Anti-PD-1 Therapy in Cancer. Clinical cancer research : an official journal of the American Association for Cancer Research 494 28619999
2017 Structural Biology of the Immune Checkpoint Receptor PD-1 and Its Ligands PD-L1/PD-L2. Structure (London, England : 1993) 298 28768162
2010 PD-L1 and PD-L2 differ in their molecular mechanisms of interaction with PD-1. International immunology 192 20587542
2023 Targeting PD-L2-RGMb overcomes microbiome-related immunotherapy resistance. Nature 158 37138075
2009 PD-L1 and PD-L2 modulate airway inflammation and iNKT-cell-dependent airway hyperreactivity in opposing directions. Mucosal immunology 158 19741598
2006 PD-1/PD-L1, but not PD-1/PD-L2, interactions regulate the severity of experimental autoimmune encephalomyelitis. Journal of neuroimmunology 152 17182110
2006 Regulation of T cell activation and tolerance by PDL2. Proceedings of the National Academy of Sciences of the United States of America 134 16864790
2014 Expression of programmed cell death 1 ligand 2 (PD-L2) is a distinguishing feature of primary mediastinal (thymic) large B-cell lymphoma and associated with PDCD1LG2 copy gain. The American journal of surgical pathology 126 25025450
2017 Analysis of PD1, PDL1, PDL2 expression and T cells infiltration in 1014 gastric cancer patients. Oncoimmunology 123 29399387
2003 B7DC/PDL2 promotes tumor immunity by a PD-1-independent mechanism. The Journal of experimental medicine 123 12810690
2015 Epithelial PD-L2 Expression Marks Barrett's Esophagus and Esophageal Adenocarcinoma. Cancer immunology research 121 26081225
2010 Role of PD-L1 and PD-L2 in allergic diseases and asthma. Allergy 104 20722638
2016 Clinical significance of PD-L1 and PD-L2 copy number gains in non-small-cell lung cancer. Oncotarget 100 27050074
2005 PD-L2:PD-1 involvement in T cell proliferation, cytokine production, and integrin-mediated adhesion. European journal of immunology 99 16278812
2011 PD-L2 is expressed on activated human T cells and regulates their function. Molecular immunology 96 21752471
2024 The efficacy of chemotherapy is limited by intratumoral senescent cells expressing PD-L2. Nature cancer 90 38267628
2021 The generation of PD-L1 and PD-L2 in cancer cells: From nuclear chromatin reorganization to extracellular presentation. Acta pharmaceutica Sinica. B 88 35530130
2020 Dual targeting of PD-L1 and PD-L2 by PCED1B-AS1 via sponging hsa-miR-194-5p induces immunosuppression in hepatocellular carcinoma. Hepatology international 85 33219943
2022 Evolving landscape of PD-L2: bring new light to checkpoint immunotherapy. British journal of cancer 83 36522474
2008 Severe tuberculosis induces unbalanced up-regulation of gene networks and overexpression of IL-22, MIP-1alpha, CCL27, IP-10, CCR4, CCR5, CXCR3, PD1, PDL2, IL-3, IFN-beta, TIM1, and TLR2 but low antigen-specific cellular responses. The Journal of infectious diseases 83 18811584
2020 PD-L1 and PD-L2 Expression in Cervical Cancer: Regulation and Biomarker Potential. Frontiers in immunology 80 33424844
2019 Immune Suppression by PD-L2 against Spontaneous and Treatment-Related Antitumor Immunity. Clinical cancer research : an official journal of the American Association for Cancer Research 80 31076547
2016 Immune Profiling of Adenoid Cystic Carcinoma: PD-L2 Expression and Associations with Tumor-Infiltrating Lymphocytes. Cancer immunology research 78 27312343
2021 PD-L2 glycosylation promotes immune evasion and predicts anti-EGFR efficacy. Journal for immunotherapy of cancer 77 34697216
2017 Expression of PD-1/PD-L1 and PD-L2 in peripheral T-cells from non-small cell lung cancer patients. Oncotarget 76 29254220
2019 The structural features that distinguish PD-L2 from PD-L1 emerged in placental mammals. The Journal of biological chemistry 71 31882544
2019 Osteosarcoma cell intrinsic PD-L2 signals promote invasion and metastasis via the RhoA-ROCK-LIMK2 and autophagy pathways. Cell death & disease 68 30886151
2019 PD-L1 and PD-L2 expression correlated genes in non-small-cell lung cancer. Cancer communications (London, England) 68 31159869
2007 Expression of PD-1, PD-L1, and PD-L2 in the liver in autoimmune liver diseases. The American journal of gastroenterology 67 17311651
2006 PD-L1 and PD-L2 have distinct roles in regulating host immunity to cutaneous leishmaniasis. European journal of immunology 67 16358363
2014 PD-1, PD-L1, PD-L2 expression in the chordoma microenvironment. Journal of neuro-oncology 66 25349132
2019 JAK2/PD-L1/PD-L2 (9p24.1) amplifications in renal cell carcinomas with sarcomatoid transformation: implications for clinical management. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 60 30996253
2018 PDL2+ CD11b+ dermal dendritic cells capture topical antigen through hair follicles to prime LAP+ Tregs. Nature communications 60 30531969
2019 Correlation Between PD-L2 Expression and Clinical Outcome in Solid Cancer Patients: A Meta-Analysis. Frontiers in oncology 57 30891423
2019 A PD-L2-based immune marker signature helps to predict survival in resected pancreatic ductal adenocarcinoma. Journal for immunotherapy of cancer 57 31464648
2018 Inhibitory functions of PD-L1 and PD-L2 in the regulation of anti-tumor immunity in murine tumor microenvironment. Cancer immunology, immunotherapy : CII 57 30357491
2019 EBV microRNA-BHRF1-2-5p targets the 3'UTR of immune checkpoint ligands PD-L1 and PD-L2. Blood 56 31856276
2019 A Tumor-Specific Super-Enhancer Drives Immune Evasion by Guiding Synchronous Expression of PD-L1 and PD-L2. Cell reports 54 31825827
2021 Neutralization of PD-L2 is Essential for Overcoming Immune Checkpoint Blockade Resistance in Ovarian Cancer. Clinical cancer research : an official journal of the American Association for Cancer Research 52 34011561
2019 A high-affinity human PD-1/PD-L2 complex informs avenues for small-molecule immune checkpoint drug discovery. Proceedings of the National Academy of Sciences of the United States of America 52 31727844
2016 The role of antagonists of the PD-1:PD-L1/PD-L2 axis in head and neck cancer treatment. Oral oncology 52 27503244
2017 PD-L1 (CD274) and PD-L2 (PDCD1LG2) promoter methylation is associated with HPV infection and transcriptional repression in head and neck squamous cell carcinomas. Oncotarget 51 29416641
2017 Tumor PDCD1LG2 (PD-L2) Expression and the Lymphocytic Reaction to Colorectal Cancer. Cancer immunology research 49 29038297
2019 Smad7 Controls Immunoregulatory PDL2/1-PD1 Signaling in Intestinal Inflammation and Autoimmunity. Cell reports 47 31553906
2017 Patterns of PD-1, PD-L1, and PD-L2 expression in pediatric solid tumors. Pediatric blood & cancer 47 28488345
2008 PD-1/PD-L1, PD-1/PD-L2, and other co-inhibitory signaling pathways in transplantation. Transplant international : official journal of the European Society for Organ Transplantation 45 18662368
2017 B7-DC (PD-L2) costimulation of CD4+ T-helper 1 response via RGMb. Cellular & molecular immunology 43 28479601
2012 PD-L2 modulates asthma severity by directly decreasing dendritic cell IL-12 production. Mucosal immunology 43 23149662
2018 Identification of PD-L2, B7-H3 and CTLA-4 immune checkpoint proteins in genetic subtypes of meningioma. Oncoimmunology 41 30546952
2020 Immune suppression caused by PD-L2 expression on tumor cells in gastric cancer. Gastric cancer : official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association 39 32367440
2020 PD-L1 and PD-L2 expression in the tumor microenvironment including peritumoral tissue in primary central nervous system lymphoma. BMC cancer 38 32248797
2021 FasL+ PD-L2+ Identifies a Novel Immunosuppressive Neutrophil Population in Human Gastric Cancer That Promotes Disease Progression. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 37 34957697
2022 PD-L2 controls peripherally induced regulatory T cells by maintaining metabolic activity and Foxp3 stability. Nature communications 34 36045140
2018 Intrinsic and Extrinsic Regulation of PD-L2 Expression in Oncogene-Driven Non-Small Cell Lung Cancer. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 34 29596910
2017 PD-L2 Regulates B-1 Cell Antibody Production against Phosphorylcholine through an IL-5-Dependent Mechanism. Journal of immunology (Baltimore, Md. : 1950) 33 28768724
2018 Expression of PD-1, PD-L1, and PD-L2 in posttransplant lymphoproliferative disorder after solid organ transplantation. Leukemia & lymphoma 31 30033844
2016 PD-1, PD-L1 and PD-L2 expression in mouse prostate cancer. American journal of clinical and experimental urology 26 27069956
2013 TLR2 directing PD-L2 expression inhibit T cells response in Schistosoma japonicum infection. PloS one 25 24376539
2024 Hypoimmunogenic human iPSCs expressing HLA-G, PD-L1, and PD-L2 evade innate and adaptive immunity. Stem cell research & therapy 24 38956724
2018 Hantavirus-Driven PD-L1/PD-L2 Upregulation: An Imperfect Viral Immune Evasion Mechanism. Frontiers in immunology 24 30559738
2023 Radiomic Analysis Based on Magnetic Resonance Imaging for Predicting PD-L2 Expression in Hepatocellular Carcinoma. Cancers 23 36672315
2021 PD-L2 suppresses T cell signaling via coinhibitory microcluster formation and SHP2 phosphatase recruitment. Communications biology 23 33990697
2018 Clinicopathological analysis of PD-L2 expression in colorectal cancer. OncoTargets and therapy 22 30464512
2020 GATA2 Regulates Constitutive PD-L1 and PD-L2 Expression in Brain Tumors. Scientific reports 21 32493985
2018 High-affinity PD-1 molecules deliver improved interaction with PD-L1 and PD-L2. Cancer science 21 29890018
2017 PD-L1/PD-L2-expressing B-1 cells inhibit alloreactive T cells in mice. PloS one 21 28570665
2016 PD-L2 negatively regulates Th1-mediated immunopathology during Fasciola hepatica infection. Oncotarget 20 27783986
2010 PD-L2 induction on dendritic cells exposed to Mycobacterium avium downregulates BCG-specific T cell response. Tuberculosis (Edinburgh, Scotland) 20 21147037
2024 PD-L2 of tumor-derived exosomes mediates the immune escape of cancer cells via the impaired T cell function. Cell death & disease 19 39511147
2021 PD-L1 and PD-L2 expression status in relation to chemotherapy in primary and metastatic esophageal squamous cell carcinoma. Cancer science 19 34773342
2019 Clinicopathological, immune and molecular correlates of PD-L2 methylation in gastric adenocarcinomas. Epigenomics 19 30821175
2018 PD-L2 amplification and durable disease stabilization in patient with urothelial carcinoma receiving pembrolizumab. Oncoimmunology 19 30524881
2023 Cholinergic signaling influences the expression of immune checkpoint inhibitors, PD-L1 and PD-L2, and tumor hallmarks in human colorectal cancer tissues and cell lines. BMC cancer 18 37828429
2021 Molecular and Immune Correlates of PDCD1 (PD-1), PD-L1 (CD274), and PD-L2 (PDCD1LG2) DNA Methylation in Triple Negative Breast Cancer. Journal of immunotherapy (Hagerstown, Md. : 1997) 17 34347720
2019 Over-Expression of Immunosuppressive Molecules, PD-L1 and PD-L2, in Ulcerative Colitis Patients. Iranian journal of immunology : IJI 17 30864556
2022 Tissue and circulating PD-L2: moving from health and immune-mediated diseases to head and neck oncology. Critical reviews in oncology/hematology 16 35569724
2021 ANO9 regulates PD-L2 expression and binding ability to PD-1 in gastric cancer. Cancer science 16 33404124
2024 Matrix stiffness-dependent PD-L2 deficiency improves SMYD3/xCT-mediated ferroptosis and the efficacy of anti-PD-1 in HCC. Journal of advanced research 15 39159723
2024 SPHK1 promotes bladder cancer metastasis via PD-L2/c-Src/FAK signaling cascade. Cell death & disease 15 39284838
2022 Programmed death receptor ligand-2 (PD-L2) bearing extracellular vesicles as a new biomarker to identify early triple-negative breast cancer patients at high risk for relapse. Journal of cancer research and clinical oncology 15 35366112
2021 The Potential Advantage of Targeting Both PD-L1/PD-L2/PD-1 and IL-10-IL-10R Pathways in Acute Myeloid Leukemia. Pharmaceuticals (Basel, Switzerland) 15 34832887
2020 Programmed death-ligand 2 (PD-L2) expression in bladder cancer. Urologic oncology 14 32151519
2022 PD-L1 and PD-L2 expression in pancreatic ductal adenocarcinoma and their correlation with immune infiltrates and DNA damage response molecules. The journal of pathology. Clinical research 13 35037417
2022 Clinical Value of the PD-1/PD-L1/PD-L2 Pathway in Patients Suffering from Endometriosis. International journal of molecular sciences 13 36232911
2020 Evaluation of PD-L1, PD-L2, PD-1 and cytotoxic immune response in oral lichen planus. Oral diseases 13 32259363
2014 Copy number alterations and neoplasia-specific mutations in MELK, PDCD1LG2, TLN1, and PAX5 at 9p in different neoplasias. Genes, chromosomes & cancer 13 24664538
2023 Pan-cancer analysis identifies PD-L2 as a tumor promotor in the tumor microenvironment. Frontiers in immunology 12 37006239
2019 Silencing of PD-L2/B7-DC by Topical Application of Small Interfering RNA Inhibits Elicitation of Contact Hypersensitivity. The Journal of investigative dermatology 12 30978356
2017 Increased expression of PD-L1 and PD-L2 in dermal fibroblasts from alopecia areata mice. Journal of cellular physiology 12 28777458
2023 High PD-L2 Predicts Early Recurrence of ER-Positive Breast Cancer. JCO precision oncology 11 36652667
2021 Mifepristone inhibited the expression of B7-H2, B7-H3, B7-H4 and PD-L2 in adenomyosis. Reproductive biology and endocrinology : RB&E 11 34289871
2021 DNA Methylation Patterns in the HLA-DPB1 and PDCD1LG2 Gene Regions in Patients with Autoimmune Thyroiditis from Different Water Iodine Areas. Thyroid : official journal of the American Thyroid Association 11 34382413
2020 PD-1, CTLA4, PD-L1 and PD-L2 DNA methylation in papillary thyroid carcinoma. Immunotherapy 11 32684057
2020 Lower PDL1, PDL2, and AXL Expression on Lung Myeloid Cells Suggests Inflammatory Bias in Smoking and Chronic Obstructive Pulmonary Disease. American journal of respiratory cell and molecular biology 11 32915645

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