IL-15 is an essential mediator of peripheral NK-cell homeostasis

Blood ◽  
2003 ◽  
Vol 101 (12) ◽  
pp. 4887-4893 ◽  
Author(s):  
Thomas Ranson ◽  
Christian A. J. Vosshenrich ◽  
Erwan Corcuff ◽  
Odile Richard ◽  
Werner Müller ◽  
...  
Keyword(s):  
Nk Cells ◽  
Mhc Class I ◽  
Nk Cell ◽  
Dominant Role ◽  
Population Level ◽  
Host Cells ◽  
Class I ◽  
Cell Homeostasis ◽  
Interleukin 7 ◽  
Mhc Class I Molecules

Abstract Several distinct classes of surface receptors can, on ligand binding, transmit signals that modulate the survival, proliferation, and apoptosis of peripheral B, T, and natural killer (NK) cells. At the population level, dynamic changes in lymphocyte cell numbers are strictly regulated to maintain a steady state, a process referred to as homeostasis. Although several studies have investigated the signals that regulate B- and T-cell homeostasis, little is known about the mechanisms that control the survival and proliferation of peripheral NK cells. Using an adoptive transfer system, we have investigated the role of γc-dependent cytokines, in particular interleukin 7 (IL-7) and IL-15, and major histocompatibility complex (MHC) class I molecules in peripheral NK-cell homeostasis. We observed that IL-15 plays a dominant role in the survival of peripheral NK cells, via maintenance of the antiapoptotic factor Bcl-2. IL-15 availability, however, also plays an important role because endogenous NK cells in the recipient mice influence the behavior of adoptively transferred NK cells. Finally, although NK cells bear functional inhibitory Ly49 receptors for MHC class I molecules, the presence or absence of specific ligands on host cells did not influence the survival or homeostatic expansion of donor NK cells.

scholarly journals The Switch from Latent to Productive Infection in Epstein-Barr Virus-Infected B Cells Is Associated with Sensitization to NK Cell Killing

2006 ◽  
Vol 81 (2) ◽  
pp. 474-482 ◽  
Author(s):  
Isabel Y. Pappworth ◽  
Eddie C. Wang ◽  
Martin Rowe
Keyword(s):  
B Cells ◽  
Nk Cells ◽  
Mhc Class I ◽  
Epstein Barr Virus ◽  
Nk Cell ◽  
Class I ◽  
Inhibitory Receptors ◽  
Barr Virus ◽  
Epstein Barr ◽  
Mhc Class I Molecules

ABSTRACT Following activation of Epstein-Barr virus (EBV)-infected B cells from latent to productive (lytic) infection, there is a concomitant reduction in the level of cell surface major histocompatibility complex (MHC) class I molecules and an impaired antigen-presenting function that may facilitate evasion from EBV-specific CD8+ cytotoxic T cells. In some other herpesviruses studied, most notably human cytomegalovirus (HCMV), evasion of virus-specific CD8+ effector responses via downregulation of surface MHC class I molecules is supplemented with specific mechanisms for evading NK cells. We now report that EBV differs from HCMV in this respect. While latently infected EBV-positive B cells were resistant to lysis by two NK lines and by primary polyclonal NK cells from peripheral blood, these effectors efficiently killed cells activated into the lytic cycle. Susceptibility to NK lysis coincided not only with downregulation of HLA-A, -B, and -C molecules that bind to the KIR family of inhibitory receptors on NK cells but also with downregulation of HLA-E molecules binding the CD94/NKG2A inhibitory receptors. Conversely, ULBP-1 and CD112, ligands for the NK cell-activating receptors NKG2D and DNAM-1, respectively, were elevated. Susceptibility of the virus-producing target cells to NK cell lysis was partially reversed by blocking ULBP-1 or CD112 with specific antibodies. These results highlight a fundamental difference between EBV and HCMV with regards to evasion of innate immunity.

scholarly journals Tumorigenicity conferred to lymphoma mutant by major histocompatibility complex-encoded transporter gene.

1993 ◽  
Vol 177 (1) ◽  
pp. 201-205 ◽  
Author(s):  
L Franksson ◽  
E George ◽  
S Powis ◽  
G Butcher ◽  
J Howard ◽  
...  
Keyword(s):  
Major Histocompatibility Complex ◽  
Nk Cells ◽  
Mhc Class I ◽  
Nk Cell ◽  
Class I ◽  
Antigenic Peptides ◽  
Major Histocompatibility ◽  
Histocompatibility Complex ◽  
Mhc Class I Molecules

Presentation of antigenic peptides by major histocompatibility complex (MHC) class I molecules requires MHC-encoded molecules of the adenosine triphosphate binding cassette (ABC) family. Defects in these proteins represent a potential risk, since they are essential links in the machinery of T cell-mediated surveillance which continuously scrutinizes peptide samples of cellular proteins. Nevertheless, transfection of the mouse lymphoma mutant RMA-S with the rat ABC gene mtp2a (homologue to mouse HAM2 and human RING11), commonly termed TAP-2 genes, led to a marked increase in tumor outgrowth potential in vivo. This occurred despite restored antigen presentation and sensitivity to cytotoxic T lymphocytes, and was found to be due to escape from natural killer (NK) cell-mediated rejection. It has previously been proposed that adequate expression of self-MHC class I is one important mechanism to avoid elimination by NK cells. Our data argue that a defect in the machinery responsible for processing and loading of peptides into MHC class I molecules is sufficient to render cells sensitive to elimination by NK cells. The latter thus appear to function as a surveillance of the peptide surveillance machinery.

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 Cross-linking of MHC class I molecules on human NK cells inhibits NK cell function, segregates MHC I from the NK cell synapse, and induces intracellular phosphotyrosines

2004 ◽  
Vol 76 (1) ◽  
pp. 116-124 ◽  
Author(s):  
Gonzalo Rubio ◽  
Xavier Férez ◽  
María Sánchez-Campillo ◽  
Jesús Gálvez ◽  
Salvador Martí ◽  
...  
Keyword(s):  
Nk Cells ◽  
Mhc Class I ◽  
Cell Function ◽  
Nk Cell ◽  
Class I ◽  
Cross Linking ◽  
Mhc I ◽  
Cell Synapse ◽  
Mhc Class I Molecules

scholarly journals MHC-dependent inhibition of uterine NK cells impedes fetal growth and decidual vascular remodelling

2014 ◽  
Vol 5 (1) ◽  
Author(s):  
Jens Kieckbusch ◽  
Louise M. Gaynor ◽  
Ashley Moffett ◽  
Francesco Colucci
Keyword(s):  
Nk Cells ◽  
Mhc Class I ◽  
Fetal Growth ◽  
Cell Function ◽  
Nk Cell ◽  
Class I ◽  
Parental Origin ◽  
Uterine Nk Cells ◽  
The Impact ◽  
Mhc Class I Molecules

Abstract NK cells express variable receptors that engage polymorphic MHC class I molecules and regulate their function. Maternal NK cells accumulate at the maternal-fetal interface and can interact with MHC class I molecules from both parents. The relative contribution of the two sets of parental MHC molecules to uterine NK cell function is unknown. Here we show that, in mice, maternal and not paternal MHC educates uterine NK cells to mature and acquire functional competence. The presence of an additional MHC allele that binds more inhibitory than activating NK cell receptors results in suppressed NK cell function, compromised uterine arterial remodelling and reduced fetal growth. Notably, reduced fetal growth occurs irrespectively of the parental origin of the inhibitory MHC. This provides biological evidence for the impact of MHC-dependent NK inhibition as a risk factor for human pregnancy-related complications associated with impaired arterial remodelling.

The strength of inhibitory input during education quantitatively tunes the functional responsiveness of individual natural killer cells

Blood ◽  
2009 ◽  
Vol 113 (11) ◽  
pp. 2434-2441 ◽  
Author(s):  
Petter Brodin ◽  
Tadepally Lakshmikanth ◽  
Sofia Johansson ◽  
Klas Kärre ◽  
Petter Höglund
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Mhc Class I ◽  
Nk Cell ◽  
Interferon Γ ◽  
Class I ◽  
Inhibitory Input ◽  
Missing Self ◽  
Functional Responsiveness ◽  
Mhc Class I Molecules

Natural killer (NK) cells express inhibitory receptors for major histocompatibility complex (MHC) class I. If self-MHC is down-regulated or absent, lack of inhibition triggers “missing self” killing. NK cells developing in the absence of MHC class I are hypo-responsive, demonstrating that MHC class I molecules are required for NK-cell education. Here, we show that the number and the type of MHC class I alleles that are present during NK-cell education quantitatively determine the frequency of responding NK cells, the number of effector functions in individual NK cells, and the amount of interferon-γ production in NK cells of specific Ly49 subsets. A relationship between the extent of inhibitory signals during education and functional responsiveness was corroborated by an enhanced probability of NK cells expressing more than one inhibitory receptor for a single host self–MHC class I allele to degranulate after activation. Our data suggest that the capacity of an individual NK cell to respond to stimulation is quantitatively controlled by the extent of inhibitory signals that are received from MHC class I molecules during NK-cell education.

scholarly journals Ly-49-independent natural killer (NK) cell specificity revealed by NK cell clones derived from p53-deficient mice.

1995 ◽  
Vol 181 (5) ◽  
pp. 1785-1795 ◽  
Author(s):  
F M Karlhofer ◽  
M M Orihuela ◽  
W M Yokoyama
Keyword(s):  
T Cell ◽  
Cell Surface ◽  
Nk Cells ◽  
Mhc Class I ◽  
Target Cell ◽  
Nk Cell ◽  
Class I ◽  
Cell Specificity ◽  
Cell Clones ◽  
Mhc Class I Molecules

Natural killer (NK) cells are heterogeneous in their specificity and expression of cell surface molecules. In the mouse, the Ly-49A molecule is a primary determinant of NK cell specificity because of its ability to downregulate NK cell activation after physical interaction with target cell MHC class I molecules. Ly-49A is expressed on an NK cell subset, and it belongs to a family of highly related molecules that may similarly dictate major histocompatibility complex (MHC) class I-associated specificity of Ly-49A- NK cells. It is not known, however, whether murine NK cell specificity may occur independently of the Ly-49 family and target cell MHC class I molecules. Similar to the impact of cloned murine T cell lines on molecular description of T cell recognition, derivation of cloned murine NK cells should permit dissection of NK cell specificity but, to date, it has not been possible to produce such effector cells. In this study, we derived NK cell clones from mice that were homozygous for a mutation in the p53 tumor suppressor gene. The cloned cells displayed the molecular, cell surface, and functional phenotype of NK cells. Significantly, the NK cell clones displayed clonal differences in ability to kill a panel of murine tumor targets and did not lyse normal cells. Target lysis was unaffected by target cell MHC class I expression, and none of the clones expressed Ly-49A on the cell surface or transcripts for Ly-49 isoforms. Although consistent with the possibility that NK cell specificity for MHC class I molecules is mediated by the Ly-49 family of molecules, the results indicate that NK cell specificity also is regulated by a mechanism independent of target cell MHC class I and the Ly-49 family.

scholarly journals Expression of Natural Killer Receptor Alleles at Different Ly49 Loci Occurs Independently and Is Regulated by Major Histocompatibility Complex Class I Molecules

2001 ◽  
Vol 193 (3) ◽  
pp. 307-316 ◽  
Author(s):  
Dawn M. Tanamachi ◽  
Thomas Hanke ◽  
Hisao Takizawa ◽  
Amanda M. Jamieson ◽  
David H. Raulet
Keyword(s):  
Major Histocompatibility Complex ◽  
Nk Cells ◽  
Natural Killer ◽  
Mhc Class I ◽  
Host Cells ◽  
Class I ◽  
Major Histocompatibility ◽  
Biallelic Expression ◽  
Histocompatibility Complex ◽  
Mhc Class I Molecules

Ly49 receptor genes are expressed by subsets of natural killer (NK) cells in an overlapping fashion, accounting for the capacity of NK subsets to attack host cells that have selectively downregulated self–major histocompatibility complex (MHC) class I molecules. It was shown previously that most NK cells express only one or the other allele of a given Ly49 gene, while a smaller population expresses both alleles. However, the methods used to detect monoallelic and biallelic cells were nonquantitative. Here, new allele-specific antibodies were used to provide the first quantitative examination of biallelic and monoallelic expression of Ly49A and Ly49G2. The results demonstrate conclusively that most Ly49A+ and Ly49G2+ NK cells express the corresponding gene in a monoallelic fashion, with a smaller subset expressing both alleles. Unexpectedly, biallelic Ly49A+ NK cells were more numerous than predicted by completely independent allelic expression, suggesting some heterogeneity among NK progenitors in the potential to express a given Ly49 gene. The data also show that cells expressing one allele of Ly49G2 may express Ly49A from the same or opposite chromosome with equal likelihood, indicating that the expressed allele is chosen independently for different Ly49 genes. Finally, the data demonstrate that biallelic expression of Ly49A or Ly49G2 occurs least frequently in mice that express ligands for these receptors (H-2d mice), and most frequently in class I–deficient mice. Thus, biallelic expression of Ly49 genes is regulated by interactions of NK cell progenitors with MHC class I molecules.

scholarly journals ERAP1 Controls the Interaction of the Inhibitory Receptor KIR3DL1 With HLA-B51:01 by Affecting Natural Killer Cell Function

2021 ◽  
Vol 12 ◽  
Author(s):  
Silvia D’Amico ◽  
Valerio D’Alicandro ◽  
Mirco Compagnone ◽  
Patrizia Tempora ◽  
Giusy Guida ◽  
...  
Keyword(s):  
Mhc Class I ◽  
Cell Function ◽  
Nk Cell ◽  
Killer Cell ◽  
Cell Subset ◽  
Human Tumor ◽  
Hla Class I ◽  
Class I ◽  
Pharmacological Inhibition ◽  
Mhc Class I Molecules

The endoplasmic reticulum aminopeptidase ERAP1 regulates innate and adaptive immune responses by trimming peptides for presentation by major histocompatibility complex (MHC) class I molecules. Previously, we have shown that genetic or pharmacological inhibition of ERAP1 on murine and human tumor cell lines perturbs the engagement of NK cell inhibitory receptors Ly49C/I and Killer-cell Immunoglobulin-like receptors (KIRs), respectively, by their specific ligands (MHC class I molecules), thus leading to NK cell killing. However, the effect of ERAP1 inhibition in tumor cells was highly variable, suggesting that its efficacy may depend on several factors, including MHC class I typing. To identify MHC class I alleles and KIRs that are more sensitive to ERAP1 depletion, we stably silenced ERAP1 expression in human HLA class I-negative B lymphoblastoid cell line 721.221 (referred to as 221) transfected with a panel of KIR ligands (i.e. HLA-B*51:01, -Cw3, -Cw4 and -Cw7), or HLA-A2 which does not bind any KIR, and tested their ability to induce NK cell degranulation and cytotoxicity. No change in HLA class I surface expression was detected in all 221 transfectant cells after ERAP1 depletion. In contrast, CD107a expression levels were significantly increased on NK cells stimulated with 221-B*51:01 cells lacking ERAP1, particularly in the KIR3DL1-positive NK cell subset. Consistently, genetic or pharmacological inhibition of ERAP1 impaired the recognition of HLA-B*51:01 by the YTS NK cell overexpressing KIR3DL1*001, suggesting that ERAP1 inhibition renders HLA-B*51:01 molecules less eligible for binding to KIR3DL1. Overall, these results identify HLA-B*51:01/KIR3DL1 as one of the most susceptible combinations for ERAP1 inhibition, suggesting that individuals carrying HLA-B*51:01-like antigens may be candidates for immunotherapy based on pharmacological inhibition of ERAP1.

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