Stimulatory and Inhibitory Killer Ig-Like Receptor Molecules Are Expressed and Functional on Lupus T Cells

Abstract

T cells from lupus patients have hypomethylated DNA and overexpress genes normally suppressed by DNA methylation that contribute to disease pathogenesis. We found that stimulatory and inhibitory killer cell Ig-like receptor (KIR) genes are aberrantly overexpressed on experimentally demethylated T cells. We therefore asked if lupus T cells also overexpress KIR, and if the proteins are functional. T cells from lupus patients were found to overexpress KIR genes, and expression was proportional to disease activity. Abs to the stimulatory molecule KIR2DL4 triggered IFN-γ release by lupus T cells, and production was proportional to disease activity. Similarly, cross-linking the inhibitory molecule KIR3DL1 prevented the autoreactive macrophage killing that characterizes lupus T cells. These results indicate that aberrant T cell KIR expression may contribute to IFN overproduction and macrophage killing in human lupus, and they suggest that Abs to inhibitory KIR may be a treatment for this disease.

Killer cell Ig-like receptor (KIR) 3DL1 down-regulation enhances inhibition of type 1 diabetes by autoantigen-specific regulatory T cells

“…T cells normally express very few or no KIRs, although KIR expression can be detected on a small subset of T cells in patients with autoimmune diseases, such as lupus and rheumatoid arthritis (22,(26)(27)(28)(29)(30)(31). It is suspected that KIR expression on the subset of T cells in these conditions may play a role in regulating aberrant T-cell responses that are associated with the initiation and/or progression of the diseases (13,15,22,29,30). Beyond this, little is known about the role of KIRs in T cells, and expression of KIRs in Tregs has not been studied.…”

“…On the other hand, activating KIRs are implicated in conditions including active host defense against infectious organisms (23)(24)(25). Normal T cells express very few or no KIRs, but KIR expression can be detected on a small subset of T cells in patients with autoimmune diseases, such as lupus and rheumatoid arthritis (22,(26)(27)(28)(29)(30)(31). Based on these studies, it has been proposed that KIR expression may play a role in aberrant T-cell responses (13,15,22,29,30).…”

CD8 T cells express randomly selected KIRs with distinct specificities compared with NK cells

“…1 For example, CD8 T cells from patients with systemic lupus erythematosus expressed higher frequencies of KIR than those from healthy individuals. 42 Furthermore, celiac disease has been associated with the appearance of KIR ϩ intraepithelial CD8 T cells in the gut lumen, 43 and rheumatoid arthritis caused an accumulation of KIR ϩ CD28 Ϫ CD4 T cells. 21,23 Because most available antibodies against KIRs display cross-reactivity and recognize both activating and inhibitory receptor forms, the role of activating KIRs in the context of these autoimmune conditions could not be examined in detail on primary cells in those published studies.…”

Genetic polymorphisms and association of KIR-HLA system of Chinese Henan Han population and an extensive KIR gene diversity study between populations distributed worldwide

“…KIR/ HLA ligand interactions were especially diverse. And a great number of previous studies have demonstrated associations between inheritance of certain combinations of KIR and HLA genes and susceptibility to many different diseases, including viral infections, autoimmune disorder, cancers, etc [43][44][45][46]. In general, HLA-C1 was the ligand of KIR2DL2/3 and KIR2DS2, and HLA-C2 was the ligand of KIR2DL1 and KIR2DS1.…”