Education of human natural killer cells by activating killer cell immunoglobulin-like receptors

Blood ◽  
2010 ◽  
Vol 115 (6) ◽  
pp. 1166-1174 ◽  
Author(s):  
Cyril Fauriat ◽  
Martin A. Ivarsson ◽  
Hans-Gustaf Ljunggren ◽  
Karl-Johan Malmberg ◽  
Jakob Michaëlsson
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Mhc Class I ◽  
Target Cell ◽  
Nk Cell ◽  
Killer Cell ◽  
Human Leukocyte ◽  
Class I ◽  
Leukocyte Antigen ◽  
Human Natural Killer Cells

Abstract Expression of inhibitory killer cell immunoglobulin-like receptors (KIRs) specific for self–major histocompatibility complex (MHC) class I molecules provides an educational signal that generates functional natural killer (NK) cells. However, the effects of activating KIRs specific for self-MHC class I on NK-cell education remain elusive. Here, we provide evidence that the activating receptor KIR2DS1 tunes down the responsiveness of freshly isolated human NK cells to target cell stimulation in donors homozygous for human leukocyte antigen (HLA)–C2, the ligand of KIR2DS1. The tuning was apparent in KIR2DS1+ NK cells lacking expression of inhibitory KIRs and CD94/NKG2A, as well as in KIR2DS1+ NK cells coexpressing the inhibitory MHC class I–specific receptors CD94/NKG2A and KIR2DL3, but not KIR2DL1. However, the tuning of responsiveness was restricted to target cell recognition because KIR2DS1+ NK cells responded well to stimulation with exogenous cytokines. Our results provide the first example of human NK-cell education by an activating KIR and suggest that the education of NK cells via activating KIRs is a mechanism to secure tolerance that complements education via inhibitory KIRs.

scholarly journals Killer Cell Inhibitory Receptor Recognition of Human Leukocyte Antigen (HLA) Class I Blocks Formation of a pp36/PLC-γ Signaling Complex in Human Natural Killer (NK) Cells

1996 ◽  
Vol 184 (6) ◽  
pp. 2243-2250 ◽  
Author(s):  
Nicholas M. Valiante ◽  
Joseph H. Phillips ◽  
Lewis L. Lanier ◽  
Peter Parham
Keyword(s):  
Human Leukocyte Antigen ◽  
Nk Cells ◽  
Natural Killer ◽  
Nk Cell ◽  
Killer Cell ◽  
Human Leukocyte ◽  
Class I ◽  
Cell Cytotoxicity ◽  
Leukocyte Antigen ◽  
Nk Cell Cytotoxicity

The killer cell inhibitory receptors (KIR) of human natural killer (NK) cells recognize human leukocyte antigen class I molecules and inhibit NK cell cytotoxicity through their interaction with protein tyrosine phosphatases (PTP). Here, we report that KIR recognition of class I ligands inhibits distal signaling events and ultimately NK cell cytotoxicity by blocking the association of an adaptor protein (pp36) with phospholipase C-γ in NK cells. In addition, we demonstrate that pp36 can serve as a substrate in vitro for the KIR-associated PTP, PTP-1C (also called SHP-1), and that recognition of class I partially disrupts tyrosine phosphorylation of NK cell proteins, providing evidence for KIR-induced phosphatase activity.

scholarly journals Inhibitory Receptors Alter Natural Killer Cell Interactions with Target Cells Yet Allow Simultaneous Killing of Susceptible Targets

1999 ◽  
Vol 190 (7) ◽  
pp. 1005-1012 ◽  
Author(s):  
Mikael Eriksson ◽  
Guenther Leitz ◽  
Erik Fällman ◽  
Ove Axner ◽  
James C. Ryan ◽  
...  
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Mhc Class I ◽  
Optical Tweezers ◽  
Target Cell ◽  
Nk Cell ◽  
Killer Cell ◽  
Class I ◽  
Target Cells ◽  
Inhibitory Receptors

Inhibitory receptors expressed on natural killer (NK) cells abrogate positive signals upon binding corresponding major histocompatibility complex (MHC) class I molecules on various target cells. By directly micromanipulating the effector–target cell encounter using an optical tweezers system which allowed temporal and spatial control, we demonstrate that Ly49–MHC class I interactions prevent characteristic cellular responses in NK cells upon binding to target cells. Furthermore, using this system, we directly demonstrate that an NK cell already bound to a resistant target cell may simultaneously bind and kill a susceptible target cell. Thus, although Ly49-mediated inhibitory signals can prevent many types of effector responses, they do not globally inhibit cellular function, but rather the inhibitory signal is spatially restricted towards resistant targets.

Neonatal NK-cell repertoires are functionally, but not structurally, biased toward recognition of self HLA class I

Blood ◽  
2011 ◽  
Vol 117 (19) ◽  
pp. 5152-5156 ◽  
Author(s):  
Kathrin Schönberg ◽  
Johannes C. Fischer ◽  
Gesine Kögler ◽  
Markus Uhrberg
Keyword(s):  
Nk Cells ◽  
Cytokine Production ◽  
Nk Cell ◽  
Killer Cell ◽  
Human Leukocyte ◽  
Hla Class I ◽  
Class I ◽  
Structural Adaptation ◽  
Leukocyte Antigen ◽  
Kir Receptors

Abstract Human natural killer (NK)–cell repertoires are biased toward more frequent expression of inhibitory killer cell Ig-like receptor (KIR) receptors for self-human leukocyte antigen (HLA) class I. Moreover, only those NK cells that express cognate receptors for self are fully functional in terms of cytotoxicity and cytokine production. It is so far unknown whether functional education and structural adaptation to HLA class I are implemented during NK-cell development and whether both processes are mechanistically connected. Here we show that NK-cell repertoires in cord blood are not yet shaped toward increased clonal frequencies of KIR for self-HLA class I as determined for the 3 major KIR ligands C1, C2, and Bw4. Nonetheless, neonatal NK cells expressing cognate KIR exhibited enhanced effector function on the level of degranulation and cytokine production. The study suggests that functional education of cognate KIR by self-HLA class I precedes structural adaptation of KIR repertoires and that both processes are not directly linked to each other.

scholarly journals Evolution and Immunogenetics of Natural Killer Cell Receptors in Health and Disease

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. SCI-25-SCI-25
Author(s):  
Peter Parham
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Mhc Class I ◽  
Nk Cell ◽  
Killer Cell ◽  
Hla Class I ◽  
Class I ◽  
Mhc Class I Molecules ◽  
Kir Gene ◽  
Kir Haplotypes

Abstract Natural killer (NK) cells are phenotypically diverse lymphocytes that contribute to innate immunity, adaptive immunity and placental reproduction. Unlike B and T cells, NK cells do not use rearranging genes to make diverse antigen receptors that are clonally expressed. Instead, NK cells express diverse combinations of a variety of receptors that are encoded by conventional non-rearranging genes. Several of these receptors are specific for conserved and variable determinants of major histocompatibility complex (MHC) class I molecules. In humans, the killer-cell immunoglobulin-like receptors (KIR) are a diverse and polymorphic family of NK-cell receptors that recognize determinants of human leukocyte antigen (HLA)-A, B and C, the polymorphic human MHC class I molecules. HLA-A, B and C are the most polymorphic of human genes, and they correlate with susceptibility to a wide range of diseases and clinical outcomes, including allogeneic hematopoietic cell transplantation (HCT). During NK-cell development, interactions between epitopes of HLA class I and KIR educate the NK cells to recognize the normal expression of these epitopes on healthy cells, and to respond to unhealthy cells in which that expression is perturbed. In the context of HCT, certain types of HLA class I mismatch enable donor-derived NK cells to make an alloreactive and beneficial graft-versus-leukemia response. Although it is likely that all placental mammals have NK cells, only a small minority of these species has a diverse KIR family like that in humans. These comprise the simian primates: New World monkeys, Old World monkeys and the great apes. Under pressure from diverse and rapidly evolving pathogens, both the MHC class I and KIR gene families have been driven to evolve rapidly. Consequently, much of their character is species-specific. This is especially true for the human KIR gene family, which is qualitatively different from that of our closest relatives, the chimpanzees. Whereas chimpanzee KIR haplotype diversity represents variations on a theme of genes encoding robust MHC class I receptors, humans have an even balance between group A KIR haplotypes encoding robust HLA class I receptors and group B KIR haplotypes encoding receptors that, to varying degree, have been subject to natural selection for reduced functional recognition of HLA class I. A balance of A and B is present in all human populations and thus appears essential for the long-term survival and competitiveness of human communities. Whereas the A KIR haplotypes correlate with successful defense against viral infection, maternal B KIR haplotypes correlate with reproductive success and donor B KIR haplotypes improve the outcome of allogeneic HCT as therapy for acute myeloid leukemia. Disclosures No relevant conflicts of interest to declare.

scholarly journals Structural plasticity of KIR2DL2 and KIR2DL3 enables altered docking geometries atop HLA-C

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Shoeib Moradi ◽  
Sanda Stankovic ◽  
Geraldine M. O’Connor ◽  
Phillip Pymm ◽  
Bruce J. MacLachlan ◽  
...  
Keyword(s):  
Natural Killer Cells ◽  
Human Leukocyte Antigen ◽  
Nk Cells ◽  
Natural Killer ◽  
Crystal Structures ◽  
Killer Cell ◽  
Human Leukocyte ◽  
Leukocyte Antigen ◽  
Functional Differences ◽  
Molecular Bases

AbstractThe closely related inhibitory killer-cell immunoglobulin-like receptors (KIR), KIR2DL2 and KIR2DL3, regulate the activation of natural killer cells (NK) by interacting with the human leukocyte antigen-C1 (HLA-C1) group of molecules. KIR2DL2, KIR2DL3 and HLA-C1 are highly polymorphic, with this variation being associated with differences in the onset and progression of some human diseases. However, the molecular bases underlying these associations remain unresolved. Here, we determined the crystal structures of KIR2DL2 and KIR2DL3 in complex with HLA-C*07:02 presenting a self-epitope. KIR2DL2 differed from KIR2DL3 in docking modality over HLA-C*07:02 that correlates with variabilty of recognition of HLA-C1 allotypes. Mutagenesis assays indicated differences in the mechanism of HLA-C1 allotype recognition by KIR2DL2 and KIR2DL3. Similarly, HLA-C1 allotypes differed markedly in their capacity to inhibit activation of primary NK cells. These functional differences derive, in part, from KIR2DS2 suggesting KIR2DL2 and KIR2DL3 binding geometries combine with other factors to distinguish HLA-C1 functional recognition.

scholarly journals The molecular basis of how buried human leukocyte antigen polymorphism modulates natural killer cell function

2020 ◽  
Vol 117 (21) ◽  
pp. 11636-11647 ◽  
Author(s):  
Philippa M. Saunders ◽  
Bruce J. MacLachlan ◽  
Phillip Pymm ◽  
Patricia T. Illing ◽  
Yuanchen Deng ◽  
...  
Keyword(s):  
Human Leukocyte Antigen ◽  
Natural Killer ◽  
Nk Cell ◽  
Killer Cell ◽  
Peptide Binding ◽  
Human Leukocyte ◽  
Hla Class I ◽  
Cell Recognition ◽  
Leukocyte Antigen ◽  
Binding Cleft

Micropolymorphisms within human leukocyte antigen (HLA) class I molecules can change the architecture of the peptide-binding cleft, leading to differences in peptide presentation and T cell recognition. The impact of such HLA variation on natural killer (NK) cell recognition remains unclear. Given the differential association of HLA-B*57:01 and HLA-B*57:03 with the control of HIV, recognition of these HLA-B57 allomorphs by the killer cell immunoglobulin-like receptor (KIR) 3DL1 was compared. Despite differing by only two polymorphic residues, both buried within the peptide-binding cleft, HLA-B*57:01 more potently inhibited NK cell activation. Direct-binding studies showed KIR3DL1 to preferentially recognize HLA-B*57:01, particularly when presenting peptides with positively charged position (P)Ω-2 residues. In HLA-B*57:01, charged PΩ-2 residues were oriented toward the peptide-binding cleft and away from KIR3DL1. In HLA-B*57:03, the charged PΩ-2 residues protruded out from the cleft and directly impacted KIR3DL1 engagement. Accordingly, KIR3DL1 recognition of HLA class I ligands is modulated by both the peptide sequence and conformation, as determined by the HLA polymorphic framework, providing a rationale for understanding differences in clinical associations.

scholarly journals Recognition of virus-infected cells by natural killer cell clones is controlled by polymorphic target cell elements.

1993 ◽  
Vol 178 (3) ◽  
pp. 961-969 ◽  
Author(s):  
M S Malnati ◽  
P Lusso ◽  
E Ciccone ◽  
A Moretta ◽  
L Moretta ◽  
...  
Keyword(s):  
T Cells ◽  
Nk Cells ◽  
Natural Killer ◽  
Target Cell ◽  
Nk Cell ◽  
Class I ◽  
Target Cells ◽  
Cell Recognition ◽  
Infected Cells ◽  
Nk Cell Recognition

Natural killer (NK) cells provide a first line of defense against viral infections. The mechanisms by which NK cells recognize and eliminate infected cells are still largely unknown. To test whether target cell elements contribute to NK cell recognition of virus-infected cells, human NK cells were cloned from two unrelated donors and assayed for their ability to kill normal autologous or allogeneic cells before and after infection by human herpesvirus 6 (HHV-6), a T-lymphotropic herpesvirus. Of 132 NK clones isolated from donor 1, all displayed strong cytolytic activity against the NK-sensitive cell line K562, none killed uninfected autologous T cells, and 65 (49%) killed autologous T cells infected with HHV-6. A panel of representative NK clones from donors 1 and 2 was tested on targets obtained from four donors. A wide heterogeneity was observed in the specificity of lysis of infected target cells among the NK clones. Some clones killed none, some killed only one, and others killed more than one of the different HHV-6-infected target cells. Killing of infected targets was not due to complete absence of class I molecules because class I surface levels were only partially affected by HHV-6 infection. Thus, target cell recognition is not controlled by the effector NK cell alone, but also by polymorphic elements on the target cell that restrict NK cell recognition. Furthermore, NK clones from different donors display a variable range of specificities in their recognition of infected target cells.

scholarly journals An Essential Role for Tumor Necrosis Factor in Natural Killer Cell–mediated Tumor Rejection in the Peritoneum

1998 ◽  
Vol 188 (9) ◽  
pp. 1611-1619 ◽  
Author(s):  
Mark J. Smyth ◽  
Janice M. Kelly ◽  
Alan G. Baxter ◽  
Heinrich Körner ◽  
Jonathon D. Sedgwick
Keyword(s):  
Tumor Necrosis Factor ◽  
Nk Cells ◽  
Natural Killer ◽  
Mhc Class I ◽  
Tumor Necrosis ◽  
Nk Cell ◽  
Tumor Rejection ◽  
Class I ◽  
Deficient Mice ◽  
Necrosis Factor

Natural killer (NK) cells are thought to provide the first line of defence against tumors, particularly major histocompatibility complex (MHC) class I− variants. We have confirmed in C57BL/6 (B6) mice lacking perforin that peritoneal growth of MHC class I− RMA-S tumor cells in unprimed mice is controlled by perforin-dependent cytotoxicity mediated by CD3− NK1.1+ cells. Furthermore, we demonstrate that B6 mice lacking tumor necrosis factor (TNF) are also significantly defective in their rejection of RMA-S, despite the fact that RMA-S is insensitive to TNF in vitro and that spleen NK cells from B6 and TNF-deficient mice are equally lytic towards RMA-S. NK cell recruitment into the peritoneum was abrogated in TNF-deficient mice challenged with RMA-S or RM-1, a B6 MHC class I− prostate carcinoma, compared with B6 or perforin-deficient mice. The reduced NK cell migration to the peritoneum of TNF-deficient mice correlated with the defective NK cell response to tumor in these mice. By contrast, a lack of TNF did not affect peptide-specific cytotoxic T lymphocyte–mediated rejection of tumor from the peritoneum of preimmunized mice. Overall, these data show that NK cells delivering perforin are the major effectors of class I− tumor rejection in the peritoneum, and that TNF is specifically critical for their recruitment to the peritoneum.

scholarly journals The Bw4 public epitope of HLA-B molecules confers reactivity with natural killer cell clones that express NKB1, a putative HLA receptor.

1995 ◽  
Vol 181 (3) ◽  
pp. 1133-1144 ◽  
Author(s):  
J E Gumperz ◽  
V Litwin ◽  
J H Phillips ◽  
L L Lanier ◽  
P Parham
Keyword(s):  
Monoclonal Antibody ◽  
Nk Cells ◽  
Natural Killer ◽  
Nk Cell ◽  
Killer Cell ◽  
Inhibitory Effect ◽  
Glycosylation Site ◽  
Class I ◽  
Target Cells ◽  
Cell Clones

Although inhibition of natural killer (NK) cell-mediated lysis by the class I HLA molecules of target cells is an established phenomenon, knowledge of the features of class I molecules which induce this effect remains rudimentary. Using class I alleles HLA-B*1502 and B*1513 which differ only at residues 77-83 which define the Bw4 and Bw6 serological epitopes, we tested the hypothesis that the presence of the Bw4 epitope on class I molecules determines recognition by NKB1+ NK cells. HLA-B*1513 possesses the Bw4 epitope, whereas B*1502 has the Bw6 epitope. Lysis by NKB1+ NK cell clones of transfected target cells expressing B*1513 as the only HLA-A, -B, or -C molecule was inhibited, whereas killing of transfectants expressing B*1502 was not. Addition of an an anti-NKB1 monoclonal antibody reconstituted lysis of the targets expressing B*1513, but did not affect killing of targets bearing B*1502. The inhibitory effect of B*1513 could be similarly prevented by the addition of an anti-class I monoclonal antibody. These results show that the presence of the Bw4 epitope influences recognition of HLA-B molecules by NK cells that express NKB1, and suggest that the NKB1 molecule may act as a receptor for Bw4+ HLA-B alleles. Sequences outside of the Bw4 region must also affect recognition by NKB1+ NK cells, because lysis of transfectants expressing HLA-A*2403 or A*2501, which possess the Bw4 epitope but are in other ways substantially different from HLA-B molecules, was not increased by addition of the anti-NKB1 antibody. Asparagine 86, the single site of N-linked glycosylation on class I molecules, is in close proximity to the Bw4/Bw6 region. The glycosylation site of the Bw4-positive molecule B*5801 was mutated, and the mutant molecules tested for inhibition of NKB1+ NK cells. Inhibition that could be reversed by addition of the anti-NKB1 monoclonal antibody was observed, showing the presence of the carbohydrate moiety is not essential for class I recognition by NKB1+ NK cell clones.

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