Activating KIR3DS1: A key driver of KIR3DL1/HLA-Bw4-linked risk in CML

Killer-cell immunoglobulin-like receptors (KIRs) regulate natural killer (NK) cell development and operate by interacting with their cognate ligands, human leukocyte antigen class I (HLA-I) molecules. KIR and HLA-I gene diversity and their independent inheritance can modulate NK cell activity, thereby impacting susceptibility to hematologic malignancies.

The presence of 11 KIR genes and their cognate HLA-I ligands was examined using PCR-SSP in 100 CML patients and 181 healthy controls. The distribution of each gene and diverse KIR/HLA-I combinations was compared between the two groups.

The results of this study disclosed a notably higher frequency of the activating (a)KIR3DS1 gene, the C4T4 subset, and the T4 gene cluster in CML patients compared with controls. There was no remarkable difference between patients and controls in the various combinations of inhibitory (i)KIR genes and their corresponding HLA-I ligands. KIR3DL1(+)/HLA-Bw4(+) combination in the presence of 3DS1 was more common in patients, while the frequency of this combination in the absence of 3DS1 was more frequent among controls. Additionally, aKIR/HLA-I combinations like KIR3DS1(+)/HLA-Bw4^Thr80(+) and KIR3DS1(+)/HLA-Bw4(+) were significantly associated with CML. Conversely, healthy individuals exhibited a higher frequency of HLA-Bw4^Thr80, HLA-A Bw4, and HLA-Bw4 ligands in the absence of their activating receptor. The frequency of aKIR = 6 and aKIR/HLA-I ≥ 3 was significantly higher among patients.

Our findings point to a potential link between aKIR genes and aKIR/HLA-I combinations with susceptibility to CML, while NK cells expressing iKIRs for their cognate HLA ligands without a corresponding aKIR can mediate effective antitumor responses.