Modulation of Human Leukocyte Antigen-C by Human Cytomegalovirus Stimulates KIR2DS1 Recognition by Natural Killer Cells

Abstract

The interaction of inhibitory killer cell Ig-like receptors (KIRs) with human leukocyte antigen (HLA) class I molecules has been characterized in detail. By contrast, activating members of the KIR family, although closely related to inhibitory KIRs, appear to interact weakly, if at all, with HLA class I. KIR2DS1 is the best studied activating KIR and it interacts with C2 group HLA-C (C2-HLA-C) in some assays, but not as strongly as KIR2DL1. We used a mouse 2B4 cell reporter system, which carries NFAT-green fluorescent protein with KIR2DS1 and a modified DAP12 adaptor protein. KIR2DS1 reporter cells were not activated upon coculture with 721.221 cells transfected with different HLA-C molecules, or with interferon-γ stimulated primary dermal fibroblasts. However, KIR2DS1 reporter cells and KIR2DS1+ primary natural killer (NK) cells were activated by C2-HLA-C homozygous human fetal foreskin fibroblasts (HFFFs) but only after infection with specific clones of a clinical strain of human cytomegalovirus (HCMV). Active viral gene expression was required for activation of both cell types. Primary NKG2A−KIR2DS1+ NK cell subsets degranulated after coculture with HCMV-infected HFFFs. The W6/32 antibody to HLA class I blocked the KIR2DS1 reporter cell interaction with its ligand on HCMV-infected HFFFs but did not block interaction with KIR2DL1. This implies a differential recognition of HLA-C by KIR2DL1 and KIR2DS1. The data suggest that modulation of HLA-C by HCMV is required for a potent KIR2DS1-mediated NK cell activation.

The Dual Role of HLA-C in Tolerance and Immunity at the Maternal-Fetal Interface

“…Engagement of KIR2DS1 with HLA-C2 molecules was shown to be dependent on peptides presented by HLA-C2 (123). Importantly, modulation of HLA-C2 by HCMV peptides stimulated KIR2DS1 recognition by NK cells, providing a molecular basis for the increased degranulation response of KIR2DS1 + dNK to HCMV infection (Figure 2C) (124). Newer studies investigating the ligands binding to other activating KIR demonstrated roles for HLA-C in presenting bacterial and viral peptides to increase KIR binding and NK cell cytotoxicity.…”

Missing or altered self: human NK cell receptors that recognize HLA-C

“…Supporting this hypothesis, KIR2DS1 has been shown to recognize a viral-induced ligand on CMV infected HLA-C2 + human fibroblasts (van der Ploeg et al 2017). However, the mechanistic basis for this recognition is not fully understood and could result from changes in HLA-C glycosylation, co-presentation of HLA-C with a viral ligand or recognition of HLA-C open conformers that lack associated peptide or β 2 -microglobulin (van der Ploeg et al 2017). Several activing KIR, including KIR2DS4, have been shown to recognize an open conformer of the non-classical HLA-F (Goodridge et al 2013).…”

“…A further obstacle has been a dearth of cellular assays that can be used to probe the binding specificity of activating KIR on NK cells, and the functional response they produce. A reporter system, in which signaling through a modified activating KIR produces intracellular expression of a fluorescent protein, is an approach with potential to solve this problem (van der Ploeg et al 2017). …”

“…KIR2DS1 recognition of HLA-C2 targets has been shown in a number of experimental systems and it is the activating KIR for which the ligand specificity is most clearly defined (Table 4) (Hilton et al 2015a; Moesta et al 2010; Pende et al 2009; Stewart et al 2005; van der Ploeg et al 2017). KIR2DS1 has an affinity for C2 that is significantly lower (~50%) than that of inhibitory KIR2DL1 (Hilton et al 2012; Hilton et al 2015a; Moesta et al 2010).…”

Human Natural Killer Receptors, Co‐Receptors, and Their Ligands

“…Conversely, the genes’ presence has been associated with an increased risk of developing autoimmune diseases (Díaz‐Peña et al., ; Du, Levinson, Reed, & Rajalingam, ; Luszczek et al., ; M. Martin, Nelson, et al., ; Momot et al., ; Nelson et al., ; Suzuki et al., ; van der Slik et al., ; Yen et al., ). Indeed, recent data indicate that activating KIR protects against some viral pathogens like CMV (van der Ploeg et al., ). On the other hand, subjects that are able to control HIV‐1 viremia (elite controllers) display a genotype that it is richer in the number of activating KIRs associated with their ligands than chronically infected patients (Malnati et al., ).…”