Peptide-specific engagement of the activating NK cell receptor KIR2DS1

Abstract

The activating NK cell receptor KIR2DS1 has been shown to be involved in many disorders including autoimmune diseases, malignancies and pregnancy outcomes. However, the precise ligands and functions of this receptor remain unclear. We aimed to gain a better understanding of the factors involved in the binding of KIR2DS1 and its inhibitory counterpart KIR2DL1 to HLA class I molecules, and the consequences for KIR2DS1+ NK-cell function. A systematic screen that assessed binding to 97 HLA-I proteins confirmed that KIR2DS1-binding was narrowly restricted to HLA-C group 2 complexes, while KIR2DL1 showed a broader binding specificity. Using KIR2DS1ζ+ Jurkat reporter-cells and peptide-pulsed 721.221.TAP1KO-HLA-C*06:02 cells, we identified the synthetic peptide SRGPVHHLL presented by HLA-C*06:02 that strongly engaged KIR2DS1- and KIR2DL1-binding. Functional analysis showed that this HLA-C*06:02-presented peptide can furthermore activate primary KIR2DS1(+) NK cell clones. Thus, we demonstrated peptide-dependent binding of the activating NK cell receptor KIR2DS1, providing new insights into the underlying mechanisms involved in KIR2DS1-related disorders.

Maternal obesity alters uterine NK activity through a functional KIR2DL1/S1 imbalance

“…Our focus on KIR2D(L1/S1) stems from research showing the importance of these two receptors in controlling aspects of placental development and in their association with poor pregnancy outcomes . Notably, HLA‐C2 directed activation of KIR2DS1 and the resulting expression of GM‐CSF in KIR2DS1 + uNK promotes trophoblast invasion . Moreover, a KIR2DS1‐containing genotype (i.e.…”

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

“…dNK (but not pNK), expressing KIR2DS1 had an increased ability to degranulate in response to HCMV-infected HLA-C2 + DSC during in vitro cocultures (122). 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).…”

Conserved and variable natural killer cell receptors: diverse approaches to viral infections

“…Based on their high sequence homology, these activating KIRs share similar HLA‐C specificities. KIR2DS1 binds HLA‐C group 2, in contrast to KIR2DL1, which binds both HLA‐C group 1 and group 2 alleles . KIR2DS2 appears to have a subtly different specificity from its inhibitory counterparts KIR2DL2 and KIR2DL3, having a tyrosine for phenylalanine substitution at residue 45, adjacent to residue 44 which defines the HLA‐C specificity of the KIR molecule .…”