KIR Polymorphism Modulates the Size of the Adaptive NK Cell Pool in Human Cytomegalovirus-Infected Individuals

Abstract

Acute infection with human CMV (HCMV) induces the development of adaptive NKG2C⁺ NK cells. In some cases, large expansions of this subset, characterized by coexpression of HLA-C-specific KIR, are stably maintained during the life-long latent phase of infection. The factors that control these unusual expansions in vivo are currently unknown. In this study, the role of KIR polymorphism and expression in this process was analyzed. It is shown that strong NKG2C⁺ NK cell expansions are dominated by single KIR clones, whereas moderate expansions are frequently polyclonal (p < 0.0001). Importantly, the choice of KIR was not arbitrary but biased toward usage of HLA-C-specific KIR encoded by the centromeric part of group A (cenA) haplotypes. Consideration of KIR allelic variation and gene copy number revealed that the cenA effect was predominantly due to the HLA-C2-specific KIR2DL1 receptor; presence of KIR2DL1 on NKG2C⁺ NK cells led to significantly larger clonal expansions than the cenB-encoded KIR2DL2 (p = 0.002). Expansion of NKG2C⁺KIR2DL1⁺ NK cells was always accompanied by the cognate ligand HLA-C2. Moreover, in these donors the frequency of NKG2C⁺ NK cells correlated with the concentration of anti-HCMV IgG (r = 0.62, p = 0.008), suggesting direct relevance of NKG2C⁺KIR2DL1⁺ NK cells for virus control. Altogether, the study suggests that the homeostasis of NKG2C⁺ NK cells in HCMV infection is at least partly controlled by coexpression of cognate inhibitory KIR. In particular, the strong interaction of KIR2DL1 and HLA-C2 ligands seems to promote large and stable expansion of adaptive NK cells in HCMV infection.