Reduced Inhibitory KIR Receptors in Patients with NK-Lymphoproliferative Disease of Large Granular Lymphocytes (NK-LDGL) Leads to Dysregulated Killing.

NK-LDGL is associated with the expansion of CD3⁻, CD16⁺ and/or CD56⁺ lymphocytes, which express a skewed repertoire of NK receptors. (

Semi-quantitative RT-PCR demonstrated that lower than normal levels of RNA of the inhibitory KIR was present in some patients in contrast to normal NK cells. Consistent with a high level of activating receptors, we found the NK-LDGL cells have potent cytolytic function in both direct and redirected cytotoxicity assays. Overexpression of activating receptors in the absence of the appropriate inhibitory receptors may contribute to the bone marrow suppression commonly observed in these patients. We first performed Class I typing of the HLA-C locus of five patients with NK-LDGL using PCR-SSP (One Lambda, Inc, Canoga Park, CA). Phenotypes included Cw05/Cw16, Cw15/15, Cw07/12, Cw04/08, and Cw02/03. Each of the five patients had lower then normal levels of inhibitory KIR (KIR2DL1 and KIR2DL2/3) by flow-cytometry and by RT-PCR. In one patient, we examined the functional ability of these inhibitory receptors to block killing of tumor cells expressing cross-reactive Class-I ligands.

Homozygous Cw15/15 was expressed by NK-LDGL5, which is a cross-reactive epitope to Cw3 and recognized by KIR2DL2/3. NK cells from NK-LDGL5 were capable of killing both the class I-negative tumor target 721.221 cells and HLA-Cw3-transfected 721.221 cells suggesting that deficient levels of inhibitory KIR were expressed on the patients NK cells to block activating NK receptor-mediated killing. These results suggest that NK cells from patients with NK-LDGL could mount dysregulated autoimmune-mediated killing, which may impact disease pathogenesis.