New perspectives on the ligands and function of the killer cell immunoglobulin-like receptor KIR3DL2 in health and disease

Abstract

KIR3DL2/CD158k/p140 is a three domain killer cell immunoglobulin-like receptor incorporating cytoplasmic immunoreceptor tyrosine inhibitory motifs, expressed as a disulphide-bonded dimer. KIR3DL2 is a framework gene within the KIR locus and is highly polymorphic, with 62 allelic variants possibly coding for protein reported. KIR3DL2 binds to HLA-A3 and -A11 in a peptide-dependent fashion and to B27 free heavy chain forms. In addition, KIR3DL2 can also function as an innate immune receptor for delivery of CpG DNA to TLR9 in NK cells. The increased levels of expression of KIR3DL2 compared with other KIR expressed by T cell subsets in healthy individuals suggest it may function as a default KIR receptor. KIR3DL2-expressing natural killer (NK) cells and IL17 secreting CD4 T cells have been implicated in the pathogenesis of ankylosing spondylitis. Moreover, KIR3DL2 expression delineates circulating and cutaneous lymphoma T cells in Sézary's syndrome. Here we discuss how the unique molecular attributes of KIR3DL2 impact on its function on NK and T cells and how this may relate to its role in disease.

Keywords: B272; CpG DNA; HLA-A11; HLA-A3; HLA-B27; KIR3DL2; Sézary’s syndrome; ankylosing spondylitis.

FIGURE 1

Hypothetical role of KIR3DL2 ligand interactions in inflammation. KIR3DL2 is expressed as a disulphide-bonded dimer with D0, D1, D2 immunoglobulin-like domain organization and two cytoplasmic ITIM motifs. (1) KIR3DL2 expression is induced by T cell activation and/or NK differentiation. (2) Bacterial infection may promote formation of B27 dimers (B27₂) and free heavy chains (FHC) by enhanced recycling of β2m-associated HLA class 1 by antigen presenting cells (APC). (3) B27 FHC including B27₂ could bind more strongly to KIR3DL2 than β2m-associated HLA class 1. B27 FHC are predicted to bind to KIR3DL2 via the D0 domain. (4) KIR3DL2 binding to ligand inhibits activation induced cell death driven by TCR/NK receptor ligand interactions, promoting the survival of pathogenic Th17 and NK cell subsets in disease. The D0 domain of KIR3DL2 also binds bacterial CpG DNA. CpG DNA internalized by KIR3DL2 could costimulate NK and T cell via TLR9 ligation (1 and 4).