KIR2DL3 and KIR2DL1 show similar impact on licensing of human NK cells

Killer cell immunoglobulin‐like receptor/HLA class I (KIR/HLA‐I) combinations are associated with disease risk, implicating functional roles for NK cells (NKCs) or KIR⁺ T cells. KIR/HLA‐I interactions can act through inhibition of NKC activation by target cells and NKC licensing for greater intrinsic responsiveness. We compared licensing conferred by the weaker, HLA‐C group 1/KIR2DL3, and the stronger, HLA‐C group 2/KIR2DL1, inhibitory combinations. The “rheostat model” predicts weaker licensing by HLA‐C1/KIR2DL3 interactions than HLA‐C2/KIR2DL1. We analyzed degranulation in NKC subsets expressing single and multiple receptors for HLA‐I. NKG2A had the strongest licensing impact, while KIR2DL3, KIR2DL1, and KIR3DL1 were weaker, and not significantly different to each other. Presence of one or two matched HLA‐C allotypes did not alter licensing of KIR2DL3⁺ and KIR2DL1⁺ NKC. Coexpression of activating KIR2DS1 disarmed KIR2DL3⁺ and KIR2DL1⁺ NKC to a similar extent. KIR3DL1 and NKG2A combined for more enhanced licensing of double‐positive NKC than the combination of KIR2DL3 and KIR2DL1. Thus, KIR2DL3 and KIR2DL1 have similar capacity to license NKC, suggesting that inhibitory signal strength and amount of available HLA‐C ligands do not correlate with NKC licensing. Altogether, our results show that the basis for disease associations of HLA‐C and KIR2DL likely encompasses factors other than licensing.     

Interaction of a dengue virus NS1‐derived peptide with the inhibitory receptor KIR3DL1 on natural killer cells

Killer immunoglobulin‐like receptors (KIRs) interact with human leucocyte antigen (HLA) class I ligands and play a key role in the regulation and activation of NK cells. The functional importance of KIR–HLA interactions has been demonstrated for a number of chronic viral infections, but to date only a few studies have been performed in the context of acute self‐limited viral infections. During our investigation of CD8⁺ T cell responses to a conserved HLA‐B57‐restricted epitope derived from dengue virus (DENV) non‐structural protein‐1 (NS1), we observed substantial binding of the tetrameric complex to non‐T/non‐B lymphocytes in peripheral blood mononuclear cells (PBMC) from a long‐standing clinical cohort in Thailand. We confirmed binding of the NS1 tetramer to CD56^dim NK cells, which are known to express KIRs. Using depletion studies and KIR‐transfected cell lines, we demonstrated further that the NS1 tetramer bound the inhibitory receptor KIR3DL1. Phenotypical analysis of PBMC from HLA‐B57⁺ subjects with acute DENV infection revealed marked activation of NS1 tetramer‐binding natural killer (NK) cells around the time of defervescence in subjects with severe dengue disease. Collectively, our findings indicate that subsets of NK cells are activated relatively late in the course of acute DENV illness and reveal a possible role for specific KIR–HLA interactions in the modulation of disease outcomes.     

Recognition of HLA-G by the NK cell receptor KIR2DL4 is not essential for human reproduction

A central issue of reproductive immunology in mammals is why a semi-allogeneic embryo is not rejected by the pregnant mother. This is particularly intriguing since, in different species, the early pregnant uterus is infiltrated by numerous maternal lymphocytes, predominantly NK cells. The human NK cell receptor KIR2DL4 has been implicated in the maternal tolerance to the embryo due to its recognition of HLA-G, a non-classical MHC molecule expressed preferentially in the placenta. Killer cell Ig-like receptors (KIR) are believed to participate in the natural immunity to infection and tumors, but KIR2DL4 has unique structural, functional and genetic features that could confer it a different role. However, we demonstrate here that the KIR2DL4:HLA-G interaction is not essential for human reproduction by showing that a multiparous woman lacks a KIR2DL4 gene.     

Pemphigus is associated with KIR3DL2 expression levels and provides evidence that KIR3DL2 may bind HLA‐A3 and A11 in vivo

Although HLA‐A3 and A11 have been reported to be ligands for KIR3DL2, evidence for any in vivo relevance of this interaction is still missing. To explore the functional importance of KIR3DL2 allelic variation, we analyzed the autoimmune disease pemphigus foliaceus, previously associated (lower risk) with activating KIR genes. KIR3DL2*001 was increased in patients (odds ratio (OR) = 2.04; p = 0.007). The risk was higher for the presence of both KIR3DL2*001 and HLA‐A3 or A11 (OR = 3.76, p = 0.013), providing the first evidence that HLA‐A3 and A11 may interact with KIR3DL2 in vivo. The nonsynonymous single nucleotide polymorphism 1190T (rs3745902) was associated with protection (OR = 0.52, p = 0.018). This SNP results in a threonine‐to‐methionine substitution. Individuals who have methionine in this position exhibit a lower percentage of KIR3DL2‐positive natural killer (NK) cells and also lower intensity of KIR3DL2 on expressing natural killer cells; additionally, we show that the expression of KIR3DL2 is independent of other killer cell immunoglobulin‐like receptors. Pemphigus foliaceus is a very unique complex disease strongly associated with immune‐related genes. It is the only autoimmune disease known to be endemic, showing a strong correlation with environmental factors. Our data demonstrate that this relatively unknown autoimmune disease may facilitate understanding of the molecular mechanisms of KIR3DL2 ligand recognition.     

Inhibitory 2B4 contributes to NK cell education and immunological derangements in XLP1 patients

X‐linked lymphoproliferative disease 1 (XLP1) is an inherited immunodeficiency, caused by mutations in SH2D1A encoding Signaling Lymphocyte Activation Molecule (SLAM)‐associated protein (SAP). In XLP1, 2B4, upon engagement with CD48, has inhibitory instead of activating function. This causes a selective inability of cytotoxic effectors to kill EBV‐infected cells, with dramatic clinical sequelae. Here, we investigated the NK cell education in XLP1, upon characterization of killer Ig‐like receptor (KIR)/KIR‐L genotype and phenotypic repertoire of self‐HLA class I specific inhibitory NK receptors (self‐iNKRs). We also analyzed NK‐cell cytotoxicity against CD48⁺ or CD48^? KIR‐ligand matched or autologous hematopoietic cells in XLP1 patients and healthy controls. XLP1 NK cells may show a defective phenotypic repertoire with substantial proportion of cells lacking self‐iNKR. These NK cells are cytotoxic and the inhibitory 2B4/CD48 pathway plays a major role to prevent killing of CD48⁺ EBV‐transformed B cells and M1 macrophages. Importantly, self‐iNKR defective NK cells kill CD48^? targets, such as mature DCs. Self‐iNKR^? NK cells in XLP1 patients are functional even in resting conditions, suggesting a role of the inhibitory 2B4/CD48 pathway in the education process during NK‐cell maturation. Killing of autologous mature DC by self‐iNKR defective XLP1 NK cells may impair adaptive responses, further exacerbating the patients’ immune defect.     

Increased frequency and function of KIR2DL1–3+ NK cells in primary HIV‐1 infection are determined by HLA‐C group haplotypes

The acquisition and maintenance of NK‐cell function is mediated by inhibitory killer‐cell immunoglobulin‐like receptors (KIRs) through their interaction with HLA class I molecules. Recently, HLA‐C expression levels were shown to be correlated with protection against multiple outcomes of HIV‐1 infection; however, the underlying mechanisms are poorly understood. As HLA‐C is the natural ligand for the inhibitory receptors KIR2DL1 and KIR2DL2/3, we sought to determine whether HLA‐C group haplotypes affect NK‐cell responses during primary HIV‐1 infection. The phenotypes and functional capacity of NK cells derived from HIV‐1‐positive and HIV‐1‐negative individuals were assessed (N = 42 and N = 40, respectively). HIV‐1 infection was associated with an increased frequency of KIR2DL1–3⁺ NK cells. Further analysis showed that KIR2DL1⁺ NK cells were selectively increased in individuals homozygous for HLA‐C2, while HLA‐C1‐homozygous individuals displayed increased proportions of KIR2DL2/3⁺ NK cells. KIR2DL1–3⁺ NK cells were furthermore more polyfunctional during primary HIV‐1 infection in individuals also encoding for their cognate HLA‐C group haplotypes, as measured by degranulation and IFN‐γ and TNF‐α production. These results identify a novel relationship between HLA‐C and KIR2DL⁺ NK‐cell subsets and demonstrate that HLA‐C‐mediated licensing modulates NK‐cell responses to primary HIV‐1 infection.     

The silent KIR3DP1 gene (CD158c) is transcribed and might encode a secreted receptor in a minority of humans, in whom the KIR3DP1, KIR2DL4 and KIR3DL1/KIR3DS1 genes are duplicated

Killer-cell Ig-like receptors (KIR) are structurally and functionally diverse, and enable human NK cells to survey the expression of individual HLA class I molecules, often altered in infections and tumors. Multiple events of non-reciprocal recombination have contributed to the rapid diversification of KIR. We show that approximately 4.5% of the individuals of a Caucasoid population bear a recombinant allele of KIR3DP1, officially designed KIR3DP1*004, that associates tightly with gene duplications of KIR3DP1, KIR2DL4 and KIR3DL1/KIR3DS1. The KIR3DP1 gene is normally silent, but the recombinant allele carries a novel promoter sequence and, as a consequence, is transcribed in all tested individuals. Messenger RNA of KIR3DP1*004 is made up of six exons; of these, exons 1-5 are similar to, and spliced like, those encoding the leader peptide and Ig-domains of KIR3D. By contrast, exon 6 is homologous to no other human KIR sequence, but only to possible homologs in chimpanzees and rhesus macaques, and encodes a short hydrophilic tail. The putative KIR3DP1*004 product, like those of the related genes LAIR-2 and LILRA3/ILT6/LIR4, is predicted to be secreted to the extracellular medium rather than anchored to the cell membrane.     

Peptide selectivity discriminates NK cells from KIR2DL2‐ and KIR2DL3‐positive individuals

Natural killer cells are controlled by peptide selective inhibitory receptors for MHC class I, including the killer cell immunoglobulin‐like receptors (KIRs). Despite having similar ligands, KIR2DL2 and KIR2DL3 confer different levels of protection to infectious disease. To investigate how changes in peptide repertoire may differentially affect NK cell reactivity, NK cells from KIR2DL2 and KIR2DL3 homozygous donors were tested for activity against different combinations of strong inhibitory (VAPWNSFAL), weak inhibitory (VAPWNSRAL), and antagonist peptide (VAPWNSDAL). KIR2DL3‐positive NK cells were more sensitive to changes in the peptide content of MHC class I than KIR2DL2‐positive NK cells. These differences were observed for the weakly inhibitory peptide VAPWNSRAL in single peptide and double peptide experiments (p < 0.01 and p < 0.03, respectively). More significant differences were observed in experiments using all three peptides (p < 0.0001). Mathematical modeling of the experimental data demonstrated that VAPWNSRAL was dominant over VAPWNSFAL in distinguishing KIR2DL3‐ from KIR2DL2‐positive donors. Donors with different KIR genotypes have different responses to changes in the peptide bound by MHC class I. Differences in the response to the peptide content of MHC class I may be one mechanism underlying the protective effects of different KIR genes against infectious disease.     

Hematopoietic stem cell transplantation: Improving alloreactive Bw4 donor selection by genotyping codon 86 of KIR3DL1/S1

KIR3DL1 is a natural killer (NK) cell receptor that recognizes the Bw4 epitope of human leukocyte antigen (HLA) class I molecules. Following hematopoietic stem cell transplantation for patients lacking Bw4, KIR3DL1‐expressing NK cells from Bw4‐positive donors can be alloreactive and eliminate tumor cells. However, KIR3DL1 alleles having T instead of C at nucleotide 320 (encoding leucine 86 instead of serine 86) are not expressed on the cell surface. Thus, not all individuals testing positive for KIR3DL1 are optimal donors for Bw4‐negative recipients. Therefore, we developed a method for genotyping codon 86, which was validated by its perfect correlation with NK cell phenotype for 100 donors of diverse KIR3DL1/S1 genotype. We typed 600 donors and found that ～12.2% had the KIR3DL1 gene, but did not express cell‐surface KIR3DL1. By contrast, high‐expressing allotypes were identified when haplotypes from four families with duplicated KIR3DL1/S1 genes were characterized at high resolution. Identifying donors who have KIR3DL1 but lack cell‐surface KIR3DL1 would refine donor selection. With this technique, the number of individuals identified who may not be optimal donors for Bw4‐negative patients increases by threefold, when compared with standard methods. Taken together, we propose that allele typing of killer cell Ig‐like receptor (KIR) polymorphisms should become a standard practice when selecting donors.     

The impact of killer cell immunoglobulin-like receptor (KIR) genes and human leukocyte antigen (HLA) class I ligands on predisposition or protection against prostate cancer

Natural killer (NK) cell development largely depends on killer cell immunoglobulin-like receptors (KIRs) and human leukocyte antigen (HLA) class I ligands. In the current study, we investigated the role of KIR genes, HLA ligands, and KIR-HLA combinations in vulnerability or protection against prostate cancer (PC). To analyze the frequency of 16 KIR genes and 5 HLA ligands, polymerase chain reaction with sequence-specific primers (PCR-SSP) was conducted in 150 PC patients and 200 healthy controls (CNs). KIR2DL5 (p = 0.0346, OR = 0.606, CI = 0.3916–0.9336), KIR2DS5 (p = 0.0227, OR = 0.587, CI = 0.3793–0.9139), HLA-B Bw4^Thr80 (p = 0.0401, OR = 0.3552, CI = 0.1466–0.9059), HLA Bw4 (p = 0.0190, OR = 0.4744, CI = 0.2656–0.8521), and T4 gene cluster (including KIR2DS5-2DL5-3DS1-2DS1 genes) (p = 0.0194, OR = 0.5575, CI = 0.3449–0.8938) had a lower frequency in the PC patients compared to the control group. Moreover, a lower frequency of the genotypes contacting activating KIR (aKIR) > inhibitory KIR (iKIR) (p = 0.0298, OR = 0.5291, CI = 0.3056–0.9174) and iKIR + HLA < aKIR + HLA (p = 0.0183, OR = 0.2197, CI = 0.0672–0.7001) in PC patients compared to the CNs implies a protective role for aKIR genes. In the case of KIR-HLA interactions, we detected a significant association between KIR3DS1⁺ + HLA-A Bw4⁺ (p = 0.0113, OR = 0.5093, CI = 0.3124–0.8416) and KIR3DL1^? + HLA-A Bw4⁺ (p = 0.0306, OR = 0.1153, CI = 0.0106–0.6537) combinations and resistance to prostate cancer. In contrast, the presence of KIR3DL1 in the absence of HLA-A Bw4 (p = 0.0040, OR = 2.00, CI = 1.264–3.111), HLA Bw4 (p = 0.0296, OR = 2.066, CI = 1.094–3.906), and HLA-Bw4^Thr80 (p = 0.0071, OR = 2.505, CI = 1.319–4.703) genes probably predisposes to prostate cancer. Carrying the CxT4 genotype in PC patients was positively associated with lower tumor grades (Gleason score ≤ 6) (p = 0.0331, OR = 3.290, and CI = 1.181–8.395). Altogether, our data suggest a protective role for aKIRs, HLA-B Bw4^Thr80, and HLA Bw4 ligands as well as a predisposing role for certain KIR-HLA combinations in prostate cancer. The findings of this study offer new insight into the population's risk assessment for prostate cancer in men. Additionally, predicting immunotherapy response based on KIR-HLA combinations aids in implementing the most effective therapeutic approach in the early stages of the disease.     

Natural killer (NK) cell activity during HIV infection: a decrease in NK activity is observed at the clonal level and is not restored after in vitro long-term culture of NK cells.

NK cell activity is impaired in HIV-infected patients. The mechanisms behind the altered NK functions are not clear, and conflicting data concerning NK and antibody-dependent cellular cytotoxicity (ADCC) activity have been reported. In order to investigate whether this impairment is also observed at the clonal level and whether it is related to a defect at the target cell binding and/or the post-binding level, we evaluated highly purified NK cell lines and cloned NK cells obtained from 22 HIV-infected patients at different stages of disease and compared them with normal controls for their ability to: (i) kill K-562 and U-937 cell lines using a 51Cr release assay; (ii) bind and kill K-562 and U-937 cells at the single cell binding level; (iii) release NK cytotoxic factor (NKCF), tumour necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma); (iv) kill anti-IgM preincubated Daudi cell line (ADCC activity). This study with cloned NK cells or NK cell lines from HIV-infected individuals showed: (i) a decrease in their lytic capability against target cell lines; (ii) a low ability to form conjugates with K-562 and U-937 cell lines with respect to controls; (iii) a decreased ability to kill bound target cells; (iv) low levels of released NKCF, TNF-alpha and IFN-gamma after incubation with U-937 cells. Taken together, these findings suggest that the impaired NK cell function during HIV infection is also observed at the clonal level and is related to defects both at the target and post-binding levels. However, the precise mechanisms remain to be determined. The inability to restore normal NK activity after long-term culture in the presence of high levels of recombinant IL-2 is in agreement with the hypothesis of a 'general anergic process' during HIV infection.     

Lower numbers of circulating natural killer T (NK T) cells in individuals with human T lymphotropic virus type 1 (HTLV‐1) associated neurological disease

Human T lymphotropic virus type 1 (HTLV‐1) infects 10–20 million people worldwide. The majority of infected individuals are asymptomatic; however, approximately 3% develop the debilitating neurological disease HTLV‐1‐associated myelopathy/tropical spastic paraparesis (HAM/TSP). There is also currently no cure, vaccine or effective therapy for HTLV‐1 infection, and the mechanisms for progression to HAM/TSP remain unclear. NK T cells are an immunoregulatory T cell subset whose frequencies and effector functions are associated critically with immunity against infectious diseases. We hypothesized that NK T cells are associated with HAM/TSP progression. We measured NK T cell frequencies and absolute numbers in individuals with HAM/TSP infection from two cohorts on two continents: São Paulo, Brazil and San Francisco, CA, USA, and found significantly lower levels when compared with healthy subjects and/or asymptomatic carriers. Also, the circulating NK T cell compartment in HAM/TSP subjects is comprised of significantly more CD4⁺ and fewer CD8⁺ cells than healthy controls. These findings suggest that lower numbers of circulating NK T cells and enrichment of the CD4⁺ NK T subset are associated with HTLV‐1 disease progression.     

Soluble HLA‐I‐mediated secretion of TGF‐β1 by human NK cells and consequent down‐regulation of anti‐tumor cytolytic activity

Soluble HLA class I (sHLA‐I) molecules can regulate survival of NK cells and their anti‐tumor killing activity. Herein, we have analysed whether interaction of sHLA‐I with CD8 and/or different isoforms of killer Ig‐like receptors (KIR) induced secretion of transforming growth factor (TGF)‐β1. CD8⁺KIR^? NK cell clones secreted TGF‐β1 upon the interaction of sHLA‐I with CD8 molecule. sHLA‐Cw4 or sHLA‐Cw3 alleles engaging inhibitory isoforms of KIR, namely KIR2DL1 or KIR2DL2, strongly downregulated TGF‐β1 production elicited through CD8. On the other hand, sHLA‐Cw4 or sHLA‐Cw3 alleles induced secretion of TGF‐β1 by ligation of stimulatory KIR2DS1 or KIR2DS2 isoforms. TGF‐β1 strongly reduced NK cell‐mediated tumor cell lysis and production of pro‐inflammatory cytokines such as TNF‐α and IFN‐γ. Also, TGF‐β1 inhibited NK cell cytolysis induced by the engagement of stimulatory receptors including NKG2D, DNAM1, 2B4, CD69, NKp30, NKp44 and NKp46. The IL‐2‐dependent surface upregulation of some of these receptors was prevented by TGF‐β1. Furthermore, TGF‐β1 hampered IL‐2‐induced NK cell proliferation but not IL‐2‐mediated rescue from apoptosis of NK cells. Depletion of TGF‐β1 restored all the NK cell‐mediated functional activities analysed. Taken together these findings suggest that sHLA‐I antigens may downregulate the NK cell‐mediated innate response by inducing TGF‐β1 release.     

Functional advantage of educated KIR2DL1+ natural killer cells for anti‐HIV‐1 antibody‐dependent activation

Evidence from the RV144 HIV‐1 vaccine trial implicates anti‐HIV‐1 antibody‐dependent cellular cytotoxicity (ADCC) in vaccine‐conferred protection from infection. Among effector cells that mediate ADCC are natural killer (NK) cells. The ability of NK cells to be activated in an antibody‐dependent manner is reliant upon several factors. In general, NK cell‐mediated antibody‐dependent activation is most robust in terminally differentiated CD57⁺ NK cells, as well as NK cells educated through ontological interactions between inhibitory killer immunoglobulin‐like receptors (KIR) and their major histocompatibility complex class I [MHC‐I or human leucocyte antigen (HLA‐I)] ligands. With regard to anti‐HIV‐1 antibody‐dependent NK cell activation, previous research has demonstrated that the epidemiologically relevant KIR3DL1/HLA‐Bw4 receptor/ligand combination confers enhanced activation potential. In the present study we assessed the ability of the KIR2DL1/HLA–C2 receptor/ligand combination to confer enhanced activation upon direct stimulation with HLA‐I‐devoid target cells or antibody‐dependent stimulation with HIV‐1 gp140‐pulsed CEM.NKr‐CCR5 target cells in the presence of an anti‐HIV‐1 antibody source. Among donors carrying the HLA‐C2 ligand for KIR2DL1, higher interferon (IFN)‐γ production was observed within KIR2DL1⁺ NK cells than in KIR2DL1^– NK cells upon both direct and antibody‐dependent stimulation. No differences in KIR2DL1⁺ and KIR2DL1^– NK cell activation were observed in HLA‐C1 homozygous donors. Additionally, higher activation in KIR2DL1⁺ than KIR2DL1^– NK cells from HLA–C2 carrying donors was observed within less differentiated CD57^– NK cells, demonstrating that the observed differences were due to education and not an overabundance of KIR2DL1⁺ NK cells within differentiated CD57⁺ NK cells. These observations are relevant for understanding the regulation of anti‐HIV‐1 antibody‐dependent NK cell responses.     

IFN‐α‐mediated increase in cytolytic activity of maturing NK cell upon exposure to HSV‐infected myelomonocytes

Impaired control of chronic pathogen replication may be associated to alterations of NK‐cell function. Whether mechanisms underlying this dysfunction involve perturbations of differentiating NK cells is still unknown. We studied an “in vitro” model of differentiation from CD34⁺Lin^? precursors growing only myelomonocytes and maturing NK cells and where myelomonocytes could be suitably infected with HSV, HIV, or vaccinia. Cultures were evaluated by cytofluorometry and cytotoxicity assays for perturbations in differentiating NK cells. Increased expression of natural cytotoxicity receptors on maturing NK cells with increased cytolytic activity was observed with HSV‐1 infection, and with vaccinia while no modulation of NK‐cell phenotype nor cytotoxic activity were evident with an ssRNA lentivirus (HIV‐1). In the presence of constant IL‐12 and IL‐15 concentrations, the observed effect did not require cell contact, involved IFN‐αand was not reproduced by the addition of TLR9 agonist, nor blocked by TLR9 antagonists. Virus replication at sites of NK‐cell precursor development may have different outcomes depending on the interaction between invading viruses and maturing NK cells. Thus, NK‐cell precursors may be involved in the immune response to dsDNA viruses and possibly contribute to efficient control of virus infection.     

Disordered expression of inhibitory receptors on the NK1-type natural killer (NK) leukaemic cells from patients with hypersensitivity to mosquito bites

Recent studies have revealed the existence of a distinct type of NK cell leukaemia of the juvenile type, which presents with hypersensitivity to mosquito bites (HMB) as an essential clinical manifestation and is infected with clonal Epstein-Barr virus (EBV). This disorder is thus called HMB-EBV-NK disease and has been reported in Orientals, mostly from Japan. We investigated the profile of cytokine production and the expression of both types of NK inhibitory receptors, i.e. CD94 lectin-like dimers and killer-cell immunoglobulin-like receptors, in NK leukaemic cells from three patients with HMB-EBV-NK disease. It was found that freshly isolated NK leukaemic cells expressed mRNA for interferon-gamma (IFN-gamma) and additionally produced IL-10 upon stimulation with IL-2, indicating that the NK cells were of NK1 type. More than 98% of NK cells from the patients bore CD94 at a higher level than did normal NK cells, whereas p70 or NKAT2, belonging to immunoglobulin-like receptor, was not expressed in those NK cells. Freshly isolated leukaemic NK cells transcribed mRNA for CD94-associated molecule NKG2C at an abnormally high level, and upon stimulation with IL-2 and/or IL-12 they expressed NKG2A as well. The disordered expression of these inhibitory receptors not only provides some insights into the pathogenesis of HMB-EBV-NK disease but also can be used as phenotypic markers for the diagnosis of this type of NK cell leukaemia.     

Activating and inhibitory killer immunoglobulin‐like receptors (KIR) in haploidentical haemopoietic stem cell transplantation to cure high‐risk leukaemias

A number of experimental studies have shown that natural killer (NK) cells can eliminate cancer cells and the mechanisms involved in this effect have been uncovered during the last two decades. Clinical data from haploidentical haematopoietic stem cell transplantation (haplo‐HSCT) revealed that NK cells were responsible for remarkably favourable effects in both adult and paediatric high‐risk leukaemias. NK receptors specific for major histocompatibility complex (MHC) class I molecules, including killer immunoglobulin (Ig)‐like receptors (KIR) and CD94/NKG2A, play a major role in the anti‐leukaemia effect (mediating either inhibitory or activating signals). Haplo‐ HSCT requires a heavy conditioning regimen for the patient and the use of large numbers of T cell‐depleted HSC to be grafted. After transplantation, natural killer cells develop from HSC shortly after engraftment and may include ‘alloreactive’ NK cells that kill leukaemic cells and prevent graft‐versus‐host disease (GvHD). Alloreactive NK cells are characterized by the expression of KIR that are not engaged by any of the human leucocyte antigen (HLA) class I alleles expressed by the patient. Their generation is dependent upon the existence of a KIR/HLA class I mismatch between donor and recipient. Novel important information on the function and specificity of different KIR has been obtained recently by the analysis of donor‐derived alloreactive NK cells in a cohort of paediatric patients given haplo‐HSCT to cure acute, high‐risk leukaemias.