scholarly journals A Signal Peptide Derived from hsp60 Binds HLA-E and Interferes with CD94/NKG2A Recognition

2002 ◽  
Vol 196 (11) ◽  
pp. 1403-1414 ◽  
Author(s):  
Jakob Michaëlsson ◽  
Cristina Teixeira de Matos ◽  
Adnane Achour ◽  
Lewis L. Lanier ◽  
Klas Kärre ◽  
...  
Keyword(s):  
Nk Cells ◽  
Mhc Class I ◽  
Signal Peptide ◽  
Nk Cell ◽  
Signal Sequence ◽  
T Cell Subsets ◽  
Class I ◽  
Dependent Manner ◽  
Mhc Class I Molecule ◽  
Stressed Cells

Human histocompatibility leukocyte antigen (HLA)-E is a nonclassical major histocompatibility complex (MHC) class I molecule which presents a restricted set of nonameric peptides, derived mainly from the signal sequence of other MHC class I molecules. It interacts with CD94/NKG2 receptors expressed on the surface of natural killer (NK) cells and T cell subsets. Here we demonstrate that HLA-E also presents a peptide derived from the leader sequence of human heat shock protein 60 (hsp60). This peptide gains access to HLA-E intracellularly, resulting in up-regulated HLA-E/hsp60 signal peptide cell-surface levels on stressed cells. Notably, HLA-E molecules in complex with the hsp60 signal peptide are no longer recognized by CD94/NKG2A inhibitory receptors. Thus, during cellular stress an increased proportion of HLA-E molecules may bind the nonprotective hsp60 signal peptide, leading to a reduced capacity to inhibit a major NK cell population. Such stress induced peptide interference would gradually uncouple CD94/NKG2A inhibitory recognition and provide a mechanism for NK cells to detect stressed cells in a peptide-dependent manner.

scholarly journals Natural killer cell education in mice with single or multiple major histocompatibility complex class I molecules

2005 ◽  
Vol 201 (7) ◽  
pp. 1145-1155 ◽  
Author(s):  
Sofia Johansson ◽  
Maria Johansson ◽  
Eleftheria Rosmaraki ◽  
Gustaf Vahlne ◽  
Ramit Mehr ◽  
...  
Keyword(s):  
Nk Cells ◽  
Mhc Class I ◽  
Nk Cell ◽  
Killer Cell ◽  
Class I ◽  
Receptor Interaction ◽  
Histocompatibility Complex ◽  
Mhc Class I Molecule ◽  
The Impact

The ability of murine NK cells to reject cells lacking self MHC class I expression results from an in vivo education process. To study the impact of individual MHC class I alleles on this process, we generated mice expressing single MHC class I alleles (Kb, Db, Dd, or Ld) or combinations of two or more alleles. All single MHC class I mice rejected MHC class I–deficient cells in an NK cell–dependent way. Expression of Kb or Dd conveyed strong rejection of MHC class I–deficient cells, whereas the expression of Db or Ld resulted in weaker responses. The educating impact of weak ligands (Db and Ld) was further attenuated by the introduction of additional MHC class I alleles, whereas strong ligands (Kb and Dd) maintained their educating impact under such conditions. An analysis of activating and inhibitory receptors in single MHC class I mice suggested that the educating impact of a given MHC class I molecule was controlled both by the number of NK cells affected and by the strength of each MHC class I–Ly49 receptor interaction, indicating that NK cell education may be regulated by a combination of qualitative and quantitative events.

scholarly journals A New Mechanism of NK Cell Cytotoxicity Activation: The CD40–CD40 Ligand Interaction

1997 ◽  
Vol 185 (12) ◽  
pp. 2053-2060 ◽  
Author(s):  
Ennio Carbone ◽  
Giuseppina Ruggiero ◽  
Giuseppe Terrazzano ◽  
Carmen Palomba ◽  
Ciro Manzo ◽  
...  
Keyword(s):  
Nk Cells ◽  
Mhc Class I ◽  
Nk Cell ◽  
Cd40 Ligand ◽  
Class I ◽  
Target Cells ◽  
Ligand Interaction ◽  
Effector Functions ◽  
Nk Cell Cytotoxicity ◽  
Dependent Pathway

NK recognition is regulated by a delicate balance between positive signals initiating their effector functions, and inhibitory signals preventing them from proceeding to cytolysis. Knowledge of the molecules responsible for positive signaling in NK cells is currently limited. We demonstrate that IL-2–activated human NK cells can express CD40 ligand (CD40L) and that recognition of CD40 on target cells can provide an activation pathway for such human NK cells. CD40-transfected P815 cells were killed by NK cell lines expressing CD40L, clones and PBLderived NK cells cultured for 18 h in the presence of IL-2, but not by CD40L-negative fresh NK cells. Cross-linking of CD40L on IL-2–activated NK cells induced redirected cytolysis of CD40-negative but Fc receptor-expressing P815 cells. The sensitivity of human TAP-deficient T2 cells could be blocked by anti-CD40 antibodies as well as by reconstitution of TAP/MHC class I expression, indicating that the CD40-dependent pathway for NK activation can be downregulated, at least in part, by MHC class I molecules on the target cells. NK cell recognition of CD40 may be important in immunoregulation as well as in immune responses against B cell malignancies.

scholarly journals MHC class I–deficient natural killer cells acquire a licensed phenotype after transfer into an MHC class I–sufficient environment

2010 ◽  
Vol 207 (10) ◽  
pp. 2073-2079 ◽  
Author(s):  
Julie M. Elliott ◽  
Joseph A. Wahle ◽  
Wayne M. Yokoyama
Keyword(s):  
Bone Marrow ◽  
Nk Cells ◽  
Natural Killer ◽  
Mhc Class I ◽  
Interferon Γ ◽  
Class I ◽  
Target Cells ◽  
Major Histocompatability Complex ◽  
Gain Of Function ◽  
Mhc Class I Molecule

In MHC class I–deficient hosts, natural killer (NK) cells are hyporesponsive to cross-linking of activation receptors. Functional competence requires engagement of a self–major histocompatability complex (MHC) class I–specific inhibitory receptor, a process referred to as “licensing.” We previously suggested that licensing is developmentally determined in the bone marrow. In this study, we find that unlicensed mature MHC class I–deficient splenic NK cells show gain-of-function and acquire a licensed phenotype after adoptive transfer into wild-type (WT) hosts. Transferred NK cells produce WT levels of interferon-γ after engagement of multiple activation receptors, and degranulate at levels equivalent to WT NK cells upon coincubation with target cells. Only NK cells expressing an inhibitory Ly49 receptor specific for a cognate host MHC class I molecule show this gain-of-function. Therefore, these findings, which may be relevant to clinical bone marrow transplantation, suggest that neither exposure to MHC class I ligands during NK development in the BM nor endogenous MHC class I expression by NK cells themselves is absolutely required for licensing.

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 Cell Surface Organization of Stress-inducible Proteins ULBP and MICA That Stimulate Human NK Cells and T Cells via NKG2D

2004 ◽  
Vol 199 (7) ◽  
pp. 1005-1010 ◽  
Author(s):  
Konstantina Eleme ◽  
Sabrina B. Taner ◽  
Björn Önfelt ◽  
Lucy M. Collinson ◽  
Fiona E. McCann ◽  
...  
Keyword(s):  
Cell Surface ◽  
Nk Cells ◽  
Lipid Rafts ◽  
Mhc Class I ◽  
Fluorescent Protein ◽  
Nk Cell ◽  
Surface Proteins ◽  
Class I ◽  
Immune Synapse ◽  
Green Fluorescent

Cell surface proteins major histocompatibility complex (MHC) class I–related chain A (MICA) and UL16-binding proteins (ULBP) 1, 2, and 3 are up-regulated upon infection or tumor transformation and can activate human natural killer (NK) cells. Patches of cross-linked raft resident ganglioside GM1 colocalized with ULBP1, 2, 3, or MICA, but not CD45. Thus, ULBPs and MICA are expressed in lipid rafts at the cell surface. Western blotting revealed that glycosylphosphatidylinositol (GPI)-anchored ULBP3 but not transmembrane MICA, MHC class I protein, or transferrin receptor, accumulated in detergent-resistant membranes containing GM1. Thus, MICA may have a weaker association with lipid rafts than ULBP3, yet both proteins accumulate at an activating human NK cell immune synapse. Target cell lipid rafts marked by green fluorescent protein–tagged GPI also accumulate with ULBP3 at some synapses. Electron microscopy reveals constitutive clusters of ULBP at the cell surface. Regarding a specific molecular basis for the organization of these proteins, ULBP1, 2, and 3 and MICA are lipid modified. ULBP1, 2, and 3 are GPI anchored, and we demonstrate here that MICA is S-acylated. Finally, expression of a truncated form of MICA that lacks the putative site for S-acylation and the cytoplasmic tail can be expressed at the cell surface, but is unable to activate NK cells.

scholarly journals Specificity of HLA class I antigen recognition by human NK clones: evidence for clonal heterogeneity, protection by self and non-self alleles, and influence of the target cell type.

1993 ◽  
Vol 178 (4) ◽  
pp. 1321-1336 ◽  
Author(s):  
V Litwin ◽  
J Gumperz ◽  
P Parham ◽  
J H Phillips ◽  
L L Lanier
Keyword(s):  
Nk Cells ◽  
Mhc Class I ◽  
Target Cell ◽  
Nk Cell ◽  
Hla Class I ◽  
Class I ◽  
Target Cells ◽  
Clonal Heterogeneity ◽  
Multiple Alleles ◽  
Wide Range

Prior studies using polyclonal populations of natural killer (NK) cells have revealed that expression of certain major histocompatibility complex (MHC) class I molecules on the membrane of normal and transformed hematopoietic target cells can prevent NK cell-mediated cytotoxicity. However, the extent of clonal heterogeneity within the NK cell population and the effect of self versus non-self MHC alleles has not been clearly established. In the present study, we have generated more than 200 independently derived human NK cell clones from four individuals of known human histocompatibility leukocyte antigens (HLA) type. NK clones were analyzed for cytolytic activity against MHC class I-deficient Epstein Barr virus (EBV) transformed B lymphoblastoid cell lines (B-LCL) stably transfected with several HLA-A, -B, or -C genes representing either self or non-self alleles. All NK clones killed the prototypic HLA-negative erythroleukemia K562 and most lysed the MHC class I-deficient C1R and 721.221 B-LCL. Analysis of the panel of HLA-A, -B, and -C transfectants supported the following general conclusions. (a) Whereas recent studies have suggested that HLA-C antigens may be preferentially recognized by NK cells, our findings indicate that 70% or more of all NK clones are able to recognize certain HLA-B alleles and many also recognize HLA-A alleles. Moreover, a single NK clone has the potential to recognize multiple alleles of HLA-A, HLA-B, and HLA-C antigens. Thus, HLA-C is not unique in conferring protection against NK lysis. (b) No simple patterns of HLA specificity emerged. Examination of a large number of NK clones from a single donor revealed overlapping, yet distinct, patterns of reactivity when a sufficiently broad panel of HLA transfectants was examined. (c) Both autologous and allogeneic HLA antigens were recognized by NK clones. There was neither evidence for deletion of NK clones reactive with self alleles nor any indication for an increased frequency of NK clones recognizing self alleles. (d) With only a few exceptions, protection conferred by transfection of HLA alleles into B-LCL was usually not absolute. Rather a continuum from essentially no protection for certain alleles (HLA-A*0201) to very striking protection for other alleles (HLA-B*5801), with a wide range of intermediate effects, was observed. (e) Whereas most NK clones retained a relatively stable HLA specificity, some NK clones demonstrated variable and heterogeneous activity over time. (f) NK cell recognition and specificity cannot be explained entirely by the presence or absence of HLA class I antigens on the target cell.(ABSTRACT TRUNCATED AT 400 WORDS)

scholarly journals Erratum: Recognition of the nonclassical MHC class I molecule H2-M3 by the receptor Ly49A regulates the licensing and activation of NK cells

2013 ◽  
Vol 14 (4) ◽  
pp. 413-413
Author(s):  
Daniel M Andrews ◽  
Lucy C Sullivan ◽  
Nikola Baschuk ◽  
Christopher J Chan ◽  
Richard Berry ◽  
...  
Keyword(s):  
Nk Cells ◽  
Mhc Class I ◽  
Class I ◽  
Mhc Class I Molecule ◽  
Nonclassical Mhc

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.

Phospholipase C-γ2 is essential for NK cell cytotoxicity and innate immunity to malignant and virally infected cells

Blood ◽  
2006 ◽  
Vol 107 (3) ◽  
pp. 994-1002 ◽  
Author(s):  
Anouk Caraux ◽  
Nayoung Kim ◽  
Sarah E. Bell ◽  
Simona Zompi ◽  
Thomas Ranson ◽  
...  
Keyword(s):  
Innate Immunity ◽  
Nk Cells ◽  
Phospholipase C ◽  
Mhc Class I ◽  
Nk Cell ◽  
Class I ◽  
Target Cells ◽  
Cell Cytotoxicity ◽  
Infected Cells ◽  
Nk Cell Cytotoxicity

AbstractPhospholipase C-γ2 (PLC-γ2) is a key component of signal transduction in leukocytes. In natural killer (NK) cells, PLC-γ2 is pivotal for cellular cytotoxicity; however, it is not known which steps of the cytolytic machinery it regulates. We found that PLC-γ2-deficient NK cells formed conjugates with target cells and polarized the microtubule-organizing center, but failed to secrete cytotoxic granules, due to defective calcium mobilization. Consequently, cytotoxicity was completely abrogated in PLC-γ2-deficient cells, regardless of whether targets expressed NKG2D ligands, missed self major histocompatibility complex (MHC) class I, or whether NK cells were stimulated with IL-2 and antibodies specific for NKR-P1C, CD16, CD244, Ly49D, and Ly49H. Defective secretion was specific to cytotoxic granules because release of IFN-γ on stimulation with IL-12 was normal. Plcg2-/- mice could not reject MHC class I-deficient lymphoma cells nor could they control CMV infection, but they effectively contained Listeria monocytogenes infection. Our results suggest that exocytosis of cytotoxic granules, but not cellular polarization toward targets, depends on intracellular calcium rise during NK cell cytotoxicity. In vivo, PLC-γ2 regulates selective facets of innate immunity because it is essential for NK cell responses to malignant and virally infected cells but not to bacterial infections.

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