Natural killer cells are well known to mediate anti-leukemic responses in myeloid leukemia but their role in myelodysplastic syndromes is not well understood. Here, in a cohort of newly diagnosed patients (n=75), widespread structural and functional natural killer cell defects were identified. One subgroup of patients (13%) had a selective deficiency of peripheral natural killer cells (count <10/mm³ blood) with normal frequencies of T and natural killer-like T cells. Natural killer cell-deficient patients were predominantly found in high-risk subgroups and deficiency of these cells was significantly associated with poor prognosis. In the second subgroup, comprising the majority of patients (76%), natural killer cells were present but exhibited poor cytotoxicity. The defect was strongly associated with reduced levels of perforin and granzyme B. Notably, natural killer cell function and arming of cytotoxic granules could be fully reconstituted by in vitro stimulation. Further phenotypic analysis of these patients revealed an immature natural killer cell compartment that was biased towards CD56^bright cells. The residual CD56^dim cells exhibited a significant increase of the unlicensed NKG2A⁻KIR⁻ subset and a striking reduction in complexity of the repertoire of killer cell immunoglobulin-like receptors. Taken together, these results suggest that the widespread defects in natural killer cell function occurring in patients with myelodysplastic syndromes are mostly due to either unsuccessful or inefficient generation of mature, functionally competent natural killer cells, which might contribute to disease progression through impaired immune surveillance.

Despite their identification several years ago, molecular identity and developmental relation between human ILC1 and NK cells, comprising group 1 ILCs, is still elusive. To unravel their connection, thorough transcriptional, epigenetic, and functional characterization was performed from umbilical cord blood (CB). Unexpectedly, ILC1-like cells lacked Tbet expression and failed to produce IFNγ. Moreover, in contrast to previously described ILC1 subsets they could be efficiently differentiated into NK cells. These were characterized by highly diversified KIR repertoires including late stage NKG2A^-KIR⁺ effector cells that are commonly not generated from previously known NK cell progenitor sources. This property was dependent on stroma cell-derived Notch ligands. The frequency of the novel ILC1-like NK cell progenitor (NKP) significantly declined in CB from early to late gestational age. The study supports a model in which circulating fetal ILC1-like NKPs travel to secondary lymphoid tissues to initiate the formation of diversified NK cell repertoires after birth.

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. Key Points KIR polymorphism crucially influences NK cell responses to HCMV. The size of NKG2C expansions correlates with loss of KIR repertoire diversity. These NKG2C expansions correlated with the HCMV-specific Ab concentration.