Killer cell lectin-like receptor subfamily G member 1 (KLRG1) (KLRG1)

Killer cell lectin-like receptor subfamily G member 1 (KLRG1) is a type II transmembrane inhibitory receptor expressed primarily on mature, late-differentiated natural killer (NK) cells and effector-memory CD8+ T cells (UniProt: Q96E93). It functions as an immune checkpoint by binding to classical cadherins, specifically E-, N-, and R-cadherins, which are often overexpressed in various epithelial tumors (PubMed: 29346718). Upon ligand binding, the immunoreceptor tyrosine-based inhibitory motif (ITIM) in the cytoplasmic tail of KLRG1 recruits phosphatases such as SHP-1 and SHP-2, which suppress activating signals and reduce the production of cytokines like IFN-gamma (PubMed: 16424191). In oncology, KLRG1 signaling is a mechanism of immune evasion, as it dampens the cytotoxic activity of NK cells and T cells within the tumor microenvironment. Therapeutic development focuses on monoclonal antibodies that block the KLRG1-cadherin axis to revitalize exhausted or senescent immune cells (ClinicalTrials.gov: NCT04374812). Beyond cancer, KLRG1 is also targeted for depletion in autoimmune diseases, such as inclusion body myositis, where KLRG1-positive T cells are implicated in tissue damage (Abcuro: ABC-008).

Other names

MAFAMast cell function-associated antigenCLEC15AC-type lectin domain family 15 member AMAFA-L

Antagonistic monoclonal antibodies block the interaction between KLRG1 and its cadherin ligands, preventing ITIM-mediated inhibitory signaling and restoring NK and T cell effector functions; alternatively, depleting antibodies target KLRG1-expressing cells for elimination.