KIR3DL2 is an inhibitory killer cell immunoglobulin-like receptor expressed on natural killer (NK) cells and T cells that functions as a receptor for MHC class I molecules, particularly HLA-A3, A11, and HLA-F open conformer 12. Upon ligand binding, KIR3DL2 negatively regulates NK and T cell effector functions through immune receptor signaling 1. Additionally, KIR3DL2 binds exogenous CpG-DNA sequences, with preferential binding to pathogen-derived DNA over self-DNA, enabling NK cells to distinguish self from pathogenic DNA 3. Beyond immune regulation, KIR3DL2 acts as a receptor on astrocytes for HLA-F, potentially protecting motor neurons from astrocyte-mediated toxicity 4. Clinically, KIR3DL2 expression serves as a biomarker for Sézary syndrome diagnosis, with ≥200 KIR3DL2+ cells/μL showing 88.6% sensitivity and 96.3% specificity 5. KIR3DL2 expression correlates with acute-type adult T-cell leukemia and is associated with promoter demethylation 6. In cancer immunotherapy, tumor-expressed IGSF8 suppresses NK cell function by binding KIR3DL2, and blocking this interaction enhances NK-mediated cytotoxicity and tumor control 7. KIR3DL2 also marks bystander CD8+ T cells activated during CAR T-cell therapy, contributing to enhanced antitumor responses 8.