JAML

JAML is a transmembrane immunoglobulin superfamily receptor that functions as a costimulatory molecule on γδ and CD8 T cells and as a context-dependent signaling scaffold in macrophages and endothelial cells. Engagement of its membrane-distal Ig domain by the epithelial ligand CXADR (CAR) through a charged, high-specificity interface recruits PI3K via a CD28-like intracellular motif, driving T cell proliferation, cytokine production, and antitumor immunity; agonistic anti-JAML antibodies synergize with PD-1 blockade to enhance tumor-infiltrating lymphocyte responses (PMID:20813954, PMID:20813955, PMID:34427588, PMID:41486351). During neutrophil transepithelial migration, JAML is proteolytically shed by zinc metalloproteases, and the released soluble ectodomain binds epithelial CAR to compromise barrier integrity and wound repair (PMID:24621992). Beyond its immune costimulatory role, JAML regulates lipid metabolism in podocytes through a SIRT1–SREBP1 axis, macrophage polarization and efferocytosis via Mincle, macrophage inflammatory signaling through PKM2/NF-κB/NLRP3, and endothelial inflammation through TRIM25-mediated ubiquitination and degradation of STAT1 (PMID:33186558, PMID:35708906, PMID:40148467, PMID:42001028).

1. 2003 Medium

   Identification of JAML as a JAM-family Ig superfamily member that localizes to cell-cell contacts and promotes leukocyte-endothelial adhesion established the gene as a junctional adhesion molecule with potential roles in immune cell trafficking.

   Evidence Molecular cloning, immunofluorescence, dimerization motif mutagenesis, and adhesion assays in myeloid leukemia cells

   PMID:12869515

   Open questions at the time

   • Endogenous ligand not identified
   • Physiological adhesion partners unknown
   • Signaling mechanism not addressed
2. 2010 High

   Discovery that JAML binds CXADR (CAR) and costimulates γδ T cells, combined with crystal structures revealing the JAML–CAR interface and intracellular PI3K recruitment via a CD28-like motif, established the core costimulatory mechanism and its structural basis.

   Evidence X-ray crystallography (apo 2.2 Å; complex 2.8 Å), binding assays, site-directed mutagenesis, PI3K recruitment biochemistry, blocking antibody, in vivo wound closure model

   PMID:20813954 PMID:20813955

   Open questions at the time

   • Downstream signaling cascade beyond PI3K not mapped
   • Role of JAML in αβ T cells versus γδ T cells not delineated
   • Whether JAML has additional ligands unresolved
3. 2011 High

   Structural characterization of a stimulatory antibody bound to JAML's membrane-proximal domain showed that agonistic signaling can be triggered from a distinct site than the CAR-binding domain, informing therapeutic antibody design.

   Evidence X-ray crystallography (2.95 Å), surface plasmon resonance, γδ T cell costimulation assays

   PMID:21220118

   Open questions at the time

   • Whether proximal-domain engagement activates identical intracellular pathways as CAR binding not resolved
   • No in vivo therapeutic testing of HL4E10
4. 2014 High

   Demonstration that JAML is shed from neutrophils by zinc metalloproteases during transepithelial migration, with soluble JAML acting as a paracrine disruptor of epithelial barriers via CAR, revealed a non-cell-autonomous pathological mode of JAML action.

   Evidence In vitro transepithelial migration, metalloprotease inhibition, anti-JAML antibody blockade, in vivo mucosal injury model

   PMID:24621992

   Open questions at the time

   • Specific metalloprotease(s) responsible for cleavage not identified
   • Cleavage site on JAML not mapped
   • Relevance to chronic inflammatory disease not tested
5. 2015 Medium

   Showing that JAML mediates monocyte and CD8 T cell transmigration across the blood-brain barrier extended its adhesion/migration function to the CNS vascular compartment.

   Evidence In vitro BBB transmigration assay with JAML blocking antibody, ex vivo and postmortem human tissue analysis

   PMID:26734656

   Open questions at the time

   • Single-lab observation without genetic confirmation
   • Ligand interaction at the BBB (CAR or other) not confirmed
   • In vivo neuroinflammation model not performed
6. 2020 High

   Podocyte-specific Jaml deletion ameliorated proteinuria and lipid accumulation in diabetic and nephrotoxic models by modulating a SIRT1–SREBP1 lipid metabolism axis, establishing a non-immune, metabolic signaling role for JAML.

   Evidence Conditional podocyte-specific Jaml KO mice in db/db, STZ, and adriamycin nephropathy models; signaling pathway analysis

   PMID:33186558

   Open questions at the time

   • How JAML engages or activates SIRT1 mechanistically unclear
   • Ligand triggering this pathway in podocytes unknown
   • Whether the metabolic role extends to other epithelia untested
7. 2021 High

   Genetic and therapeutic evidence that JAML–CXADR interaction within tumors sustains γδ and CD8 T cell antitumor function, and that an agonistic anti-JAML antibody synergizes with anti-PD-1, positioned JAML as an immunotherapy target.

   Evidence JAML KO mice with tumor implantation, agonistic antibody monotherapy and combination with anti-PD-1, flow cytometry of TIL populations

   PMID:34427588

   Open questions at the time

   • Human tumor relevance demonstrated only correlatively
   • Optimal antibody properties for clinical translation not defined
   • Whether JAML agonism activates exhausted versus naïve T cells not resolved
8. 2022 High

   Using macrophage-specific Jaml KO and bone marrow chimeras, JAML was shown to drive acute kidney injury through macrophage polarization and Mincle-dependent efferocytosis, revealing a macrophage-intrinsic inflammatory axis distinct from its T cell costimulatory function.

   Evidence Macrophage-specific and tubular-specific Jaml conditional KO mice in renal IRI and cisplatin AKI models

   PMID:35708906

   Open questions at the time

   • Direct JAML–Mincle physical interaction not demonstrated
   • Signal transduction between JAML and Mincle pathway not fully mapped
   • Whether macrophage JAML uses CXADR as ligand in this context unknown
9. 2023 Medium

   TCR engagement was shown to induce JAML expression through cis-regulatory interactions between the CD3D and JAML loci, and JAML marks tissue-resident memory CD8+ T cells in tumors, linking JAML transcriptional control to its functional niche in antitumor immunity.

   Evidence TCR stimulation, chromatin accessibility/cis-regulatory analysis, single-cell transcriptomics, murine melanoma model with agonistic antibody

   PMID:36701231

   Open questions at the time

   • Cis-regulatory mechanism single-lab, not independently confirmed
   • Transcription factor(s) mediating TCR-dependent JAML induction not identified
   • Whether this regulatory circuit operates in human tumors not shown
10. 2025 Medium

    Cell-type-specific studies revealed opposing roles for JAML in atherosclerosis: macrophage JAML promotes plaque formation via PKM2-driven NF-κB/NLRP3 inflammasome activation, while endothelial JAML suppresses vascular inflammation by facilitating TRIM25-mediated STAT1 ubiquitination and degradation.

    Evidence Macrophage-specific and endothelial-specific JAML KO/overexpression mice, co-IP (PKM2/p65; STAT1/TRIM25), RNA-seq, high-fat diet atherosclerosis models

    PMID:40148467 PMID:42001028

    Open questions at the time

    • Opposing cell-type roles from independent labs not yet reconciled in a unified model
    • Whether JAML directly binds PKM2 or TRIM25 versus acting as a scaffold unclear
    • CXADR involvement in vascular context not tested
11. 2025 Medium

    Endothelial JAML was found to promote tumor angiogenesis through FAK/SRC/AKT/ERK and VEGF/VEGFR2 signaling, with endothelial-specific JAML deletion normalizing tumor vasculature, increasing pericyte coverage, and enhancing T cell infiltration.

    Evidence Endothelial-specific JAML KO mice in multiple tumor models, HUVEC in vitro assays, western blot for pathway phosphorylation

    PMID:39983824

    Open questions at the time

    • Pro-angiogenic versus anti-inflammatory endothelial roles of JAML appear contradictory; context-dependence not resolved
    • Whether JAML directly activates FAK or acts upstream unclear
    • Single-lab finding
12. 2026 Medium

    PD-1 signaling was shown to suppress JAML expression on CD4+ tissue-resident memory T cells, with JAML required for XCL1 secretion and cDC1 recruitment; PD-1 blockade restored JAML and antitumor function, extending the JAML costimulatory axis to CD4 TRM and DC cross-talk.

    Evidence PD-1 signaling inhibition, JAML expression rescue, XCL1 functional assay, cDC1 recruitment in vivo, murine tumor model with agonistic anti-JAML plus anti-PD-1

    PMID:41486351

    Open questions at the time

    • Mechanism by which PD-1 transcriptionally represses JAML not defined
    • Single-lab observation in murine NSCLC model
    • Human clinical relevance of CD4 TRM JAML expression not validated

• A unified model integrating JAML's apparently opposing roles across different cell types (costimulatory in T cells, pro-inflammatory in macrophages, both pro-angiogenic and anti-inflammatory in endothelium, metabolic in podocytes) and the ligand dependencies in each context remains to be constructed.
• No systematic comparison of JAML signaling pathways across cell types
• Identity of ligand(s) engaging JAML in macrophages, podocytes, and endothelium unknown
• Full interactome and post-translational modification landscape not mapped