LOXL2

LOXL2 Full Name

lysyl oxidase like 2

LOXL2 Introduction

Killer cell immunoglobulin-like receptor, two domains, long cytoplasmic tail, 3 (KIR2DL3), also designated CD158b2, is an inhibitory receptor of the KIR family. Closely related to KIR2DL2 (from which it is distinguished by only a few amino acid residues in the extracellular domains), KIR2DL3 is encoded by the KIR2DL3 gene within the highly polymorphic KIR gene cluster on chromosome 19q13.4. Expressed on NK cells and T cell subsets, KIR2DL3 recognizes HLA-C allotypes bearing the Asn80 epitope (group 1 HLA-C, e.g., HLA-Cw1, -Cw3, -Cw7, -Cw8), delivering inhibitory signals that regulate NK cell-mediated cytotoxicity and cytokine production.

Figure 1. Strcuture of LOXL2.

Ligand Specificity, Affinity, and Functional Distinction from KIR2DL2
KIR2DL3 and KIR2DL2 are products of allelic genes and represent the two major inhibitory KIRs for group 1 HLA-C ligands. Despite their high sequence identity, KIR2DL3 and KIR2DL2 differ functionally: KIR2DL3 binds HLA-C group 1 ligands with lower affinity and exhibits faster dissociation kinetics compared to KIR2DL2, resulting in quantitatively distinct inhibitory signals. This affinity difference has important functional consequences — KIR2DL3 is associated with weaker NK cell education and consequently a greater capacity to respond to perturbations in HLA expression, whereas KIR2DL2 mediates stronger inhibition and more stringent NK cell licensing. These quantitative differences in inhibitory signaling strength are translated into differential clinical outcomes: individuals homozygous for KIR2DL3 and HLA-C group 1 homozygosity (a compound genotype associated with weak inhibitory signaling) demonstrate superior spontaneous clearance of acute hepatitis C virus infection, consistent with the model that weaker NK cell inhibition facilitates more robust antiviral responses.

KIR2DL3 in Infectious Disease, Autoimmunity, and Therapeutic Modulation
The KIR2DL3-HLA-C1 axis has been most extensively studied in the context of hepatitis C virus (HCV) infection, where the KIR2DL3:HLA-C1 homozygous compound genotype is strongly associated with spontaneous viral clearance. This observation has motivated investigation of NK cell checkpoint blockade — therapeutic antibodies that block inhibitory KIR-HLA interactions to unleash NK cell-mediated clearance of infected or malignant cells. The anti-KIR monoclonal antibody lirilumab (IPH2102), which blocks KIR2DL1, KIR2DL2, and KIR2DL3, has been evaluated in clinical trials for both hematological malignancies (acute myeloid leukemia, multiple myeloma) and solid tumors, in combination with immune checkpoint inhibitors (anti-PD-1) and lenalidomide. In autoimmune disease, particular KIR2DL3-HLA combinations have been associated with altered susceptibility to conditions including psoriatic arthritis, ankylosing spondylitis, and type 1 diabetes, reflecting the role of NK cells in both eliminating autoreactive cells and contributing to tissue inflammation.

Alternate Names for LOXL2

LOXL2; lysyl oxidase like 2; LOR2; WS9-14