Killer cell lectin-like receptor subfamily F member 1–Activation-induced C-type lectin axis (KLRF1–CLEC2B axis) (NKp80–AICL axis)

The NKp80–AICL axis is a critical immune-regulatory pathway consisting of the activating homodimeric C-type lectin-like receptor NKp80 (encoded by KLRF1) and its ligand, the activation-induced C-type lectin (AICL, encoded by CLEC2B). NKp80 is expressed on nearly all mature human Natural Killer (NK) cells and a subset of effector memory T cells, where its ligation triggers potent cytotoxicity and the secretion of pro-inflammatory cytokines like IFN-gamma. AICL is primarily expressed on myeloid cells, such as monocytes and macrophages, and its expression is restricted to humans, making this axis a unique target for human-specific immunotherapy. In oncology, AICL is frequently expressed on the surface of acute myeloid leukemia (AML) blasts, providing a rationale for targeting the axis to eliminate leukemic cells while sparing non-hematopoietic tissues. Conversely, in autoimmune conditions like rheumatoid arthritis, the axis contributes to chronic inflammation through the recruitment and activation of NK cells in synovial tissues, suggesting that inhibitory targeting may alleviate tissue damage.

Other names

NKp80–CLEC2B axisKLRF1–AICL interactionCLEC2B–KLRF1 axis

The axis functions through the binding of the activating receptor NKp80 (KLRF1) on Natural Killer (NK) cells to its ligand AICL (CLEC2B) on myeloid cells or tumor cells. Therapeutic strategies involve using monoclonal antibodies to either block this interaction in inflammatory contexts or to trigger antibody-dependent cellular cytotoxicity (ADCC) against AICL-expressing malignant cells, such as in acute myeloid leukemia (AML). Additionally, chimeric antigen receptors (CARs) can be engineered to target AICL-expressing cells using the extracellular domain of NKp80.