Killer cell immunoglobulin-like receptor 3DL3 (KIR3DL3)

Killer cell immunoglobulin-like receptor 3DL3 (KIR3DL3) is an inhibitory receptor and member of the killer cell immunoglobulin-like receptor (KIR) family, encoded by a polymorphic gene located in the leukocyte receptor complex on chromosome 19q13.4[1][5]. KIR3DL3 is a framework gene present on all human KIR haplotypes and is generally expressed in a subset of T cells—particularly in tissue-resident γδ and CD8+ T cells—while being rare in NK cells and peripheral blood[3][4][5]. The receptor contains three extracellular immunoglobulin domains and a long cytoplasmic tail with an immunoreceptor tyrosine-based inhibitory motif (ITIM), conferring its inhibitory function[1][5]. Its best-characterized ligand is HHLA2, a B7 family member, forming an immune checkpoint analogous to the PD1-PD-L1 pathway[3][4]. KIR3DL3-HHLA2 interaction inhibits T cell and NK cell activation, promoting immune evasion in cancer, especially where HHLA2 is highly expressed such as in clear cell renal cell carcinoma[4][5]. Therapeutic antibodies targeting this axis are under investigation as novel immuno-oncology strategies. Blockade of KIR3DL3-HHLA2 enhances antitumor immunity but may carry immune-related safety risks, similar to established checkpoint inhibitors[4].

Other names

KIR3DL7KIRC1KIR44CD158ZCD158 antigen-like family member ZKiller cell inhibitory receptor 1

Immune checkpoint inhibition by blocking KIR3DL3–HHLA2 interaction to enhance T cell and NK cell activation