Search

Natural killer (NK) cells make vital contributions to the immune system and the reproductive system. Notably, NK cells of donor origin can recognize and kill residual leukaemic cells and cure malignant patients in hematopoietic stem cell (HSC) transplant setting. NK cell function is regulated by KIRs that recognize cognate HLA class I molecules on target cells, depending on their amino acid residues. In review, we addressed the question of binding capacity and avidity of HLA class I molecules to different killer cell immunoglobulin-like receptors (KIRs) depending on all interacting amino acid residues both on HLA and KIR side. We searched PubMed database and analysed available HLA:KIR crystallographic data for amino acid residues in HLA molecules, those physically involved in binding KIRs (termed here the "entire KIR interface"). Within entire KIR interface, we selected five functional sequence motifs (14-19, 66-76, 77-84, 88-92 and 142-151) and classified them according to the conservation of their amino acid sequences among 8,942 HLA class I molecules. Although some conserved amino acid motifs were shared by different groups of KIR ligands, the HLA motif combinations were exclusive for the ligand groups. In 135 common HLA class I molecules with known HLA:KIR recognition, we found 54 combinations of five motifs in each of the KIR-binding interfaces (C1, C2, Bw4, A3/11) and conserved non-KIR-binding interfaces. Based on the entire KIR interface, this analysis allowed to classify 8,942 HLA class I molecules into KIR specificity groups. This functional and evolutionary classification of entire KIR interfaces provides a tool for unambiguously predicting HLA:KIR interactions for common and those HLA molecules that have not yet been functionally tested. Considering the entire KIR interface in HLA class I molecules, functional interactions of HLA and KIR can be predicted in immune responses, reproduction and allotransplantation. Further functional studies are needed on the HLA:KIR interaction variations caused by the repertoires of peptides presented by HLA molecules and KIR polymorphisms at allelic level.

Serious risks in unrelated hematopoietic stem cell transplantation (HSCT) including graft versus host disease (GvHD) and mortality are associated with HLA disparity between donor and recipient. The increased risks might be dependent on disparity in not-routinely-tested multiple polymorphisms in genetically dense MHC region, being organized in combinations of two extended MHC haplotypes (Ehp). We assessed the clinical role of donor-recipient Ehp disparity levels in N = 889 patients by the population-based detection of HLA allele phase mismatch. We found increased GvHD incidences and mortality rates with increasing Ehp mismatch level even with the same HLA mismatch level. In multivariate analysis HLA mismatch levels were excluded from models and Ehp disparity level remained independent prognostic factor for high grade acute GvHD (p = 0.000037, HR = 10.68, 95%CI 5.50-32.5) and extended chronic GvHD (p 0.000001, HR = 15.51, CI95% 5.36-44.8). In group with single HLA mismatch, patients with double Ehp disparity had worse 5-year overall survival (45% vs. 56%, p = 0.00065, HR = 4.05, CI95% 1.69-9.71) and non-relapse mortality (40% vs. 31%, p = 0.00037, HR = 5.63, CI95% 2.04-15.5) than patients with single Ehp disparity. We conclude that Ehp-linked factors contribute to the high morbidity and mortality in recipients given HLA-mismatched unrelated transplant and Ehp matching should be considered in clinical HSCT.

Natural killer (NK) cell licensing status depends on clonal expression of inhibitory killer cell immunoglobulin-like receptors (iKIR) and short term HLA environment. Licensed NK cells are more efficient in tumor killing than unlicensed NK cells. Cognate KIR-HLA pairs in hematopoietic stem cell transplant (HSCT) donor and recipient are decisive for the possible change in the NK cell licensing status after HSCT. We assessed clinical outcomes in 297 patients with lymphoproliferative or myeloproliferative malignancies, or myelodysplastic syndrome in a model with upward licensing, downward resetting, and unchanged licensing genetics status after T cell replate HSCT from unrelated donors. We found extremely low (0%) relapse/progression incidence (RI), and better (59%) event-free survival (EFS) in recipients with upward licensing status and highly increased RI (37.5%), and reduced EFS (8%) among patients with the downward resetting status of repopulated donor NK cells after HSCT, as compared with unchanged NK cell licensing (RI 23%, EFS 47%). These trends were confirmed in adjusted multivariable models (for RI p = 6.66E-09, OR = 1.47, 95% CI 1.29-1.66 and for EFS p = 3.79E-13, OR = 1.67, 95% CI 1.50-1.84). Differences in the incidence of acute graft versus host disease (GvHD 62, 69, and 47%) and chronic GvHD (24, 44, and 15%, respectively) in three groups were insignificant. It would be rationale the preferential selection of the donors with upward licensing over downward resetting inhibitory KIR:HLA constellation and inclusion of the KIR genotyping in the donor selection algorithm for malignant patients. Further studies using enlarged cohorts of patients with more homogenous diagnosis are essential to reliably verify these preliminary data.

Viral infections are the main cause of increased morbidity and mortality among recipients in allogeneic hematopoietic stem cell transplantation (HSCT). Natural killer (NK) cells fight virally infected cells provided directional activation of cytotoxicity. In this study, we analyzed the role of receptor-ligand pairs that include inhibitory or activating killer cell immunoglobulin-like receptors (KIRs) with their HLA class I ligands in the course of viral infections. The paper also presents an algorithm that allows performing automated inhibitory (i) KIR:HLA pairing and rechecking in the clinical setting. The obtained results indicate a significant adverse roles of reduced number of iKIR:HLA pairs (40% vs 9%; odds ratio [OR] = 6.67; P = .0057; 95% confidence interval [CI] 1.74-25.62) and the presence of activating KIR:HLA pairs (15% vs 5%, OR = 3.58, P = .028, 95% CI 1.19-10.73) in EBV infections post HSCT.

HLA are functional in cancer immunosurveillance in adaptive and innate immunity pathways. In unrelated hematopoietic stem cell transplantation (HSCT) in 688 patients with hematological malignancies we compared antitumor efficacy of transplant in three models including the level of: (a) donor-recipient HLA class I mismatch, (b) KIR-ligand mismatch, (c) post-transplant cognate HLA:KIR pairing. The effects were directly compared in multivariate models with backward elimination including all three effects in initial model. In final multivariate model HLA mismatch and KIR-ligand mismatch levels were eliminated and HLA:KIR-dependent NK cell licensing effect remained independent prognostic factor for DFS, relapse/progression incidence, and overall survival (OS). These results suggested that NK cell licensing via cognate HLA:KIR pairs is primarily functional in cancer immunosurveillance in HSCT.