KLRD1

KLRD1 encodes CD94, a type II transmembrane glycoprotein belonging to the C-type lectin domain family. Commonly forming heterodimers with NKG2 family members (e.g., NKG2A or NKG2C), CD94 functions as a regulatory receptor on natural killer (NK) cells and cytotoxic T lymphocytes. The CD94/NKG2A complex acts as an inhibitory receptor by binding to HLA-E molecules presenting leader peptides derived from MHC class I proteins, thereby downregulating cytotoxic activity when self-MHC levels are normal. This receptor-ligand interaction modulates immune tolerance and antiviral responses through the MAPK/ERK and PI3K/AKT signaling pathways, balancing immune activation and suppression. Polymorphisms in KLRD1 have been implicated in altered susceptibility to viral infections, including HIV and hepatitis C.
Dysregulation of CD94/NKG2A-mediated signaling is associated with autoimmune disorders, such as rheumatoid arthritis, and tumor immune evasion in cancers like melanoma and lung adenocarcinoma. Therapeutic strategies targeting this axis focus on blocking NKG2A to enhance NK cell antitumor activity. Monalizumab, an anti-NKG2A monoclonal antibody, has shown promising results in Phase II trials when combined with PD-(L)1 inhibitors for solid tumors. Additionally, CRISPR-based editing of KLRD1 in CAR-T therapies is being explored to improve persistence against hematological malignancies. Recent studies also highlight CD94's role in metabolic reprogramming of tumor-infiltrating lymphocytes, suggesting combinatorial approaches with metabolic modulators.