scholarly journals Acquisition of Ly49 Receptor Expression by Developing Natural Killer Cells

1998 ◽  
Vol 187 (4) ◽  
pp. 609-618 ◽  
Author(s):  
Jeffrey R. Dorfman ◽  
David H. Raulet
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Nk Cell ◽  
Receptor Expression ◽  
Class I ◽  
Cell Repertoire ◽  
Class I Mhc ◽  
Mhc Molecules ◽  
Histocompatibility Complex

The formation of the repertoire of mouse natural killer (NK) cell receptors for major histocompatibility complex (MHC) class I molecules was investigated by determining the developmental pattern of Ly49 receptor expression. During the first days after birth, few or no splenic NK cells express Ly49A, Ly49C, Ly49G2, or Ly49I receptors. The proportion of Ly49+ splenic NK cells gradually rises to adult levels during the first 6–8 wk of life. The appearance of appreciable numbers of splenic Ly49+ NK cells coincides with the appearance of NK activity at 3–4 wk. After in vivo transfer, NK cells not expressing specific Ly49 receptors can give rise to NK cells that do, and cells expressing one of these four Ly49 receptors can give rise to cells expressing others. Once initiated, expression of a Ly49 receptor is stable for at least 10 d after in vivo transfer. Hence, initiation of Ly49 receptor expression occurs successively. Interestingly, expression of one of the receptors tested, Ly49A, did not occur after in vivo transfer of Ly49A− cells. One possible explanation for these data is that the order of Ly49 receptor expression by NK cells is nonrandom. The results provide a framework for evaluating models of NK cell repertoire formation, and how the repertoire is molded by host class I MHC molecules.

scholarly journals A subset of natural killer cells achieves self-tolerance without expressing inhibitory receptors specific for self-MHC molecules

Blood ◽  
2005 ◽  
Vol 105 (11) ◽  
pp. 4416-4423 ◽  
Author(s):  
Nadine C. Fernandez ◽  
Emmanuel Treiner ◽  
Russell E. Vance ◽  
Amanda M. Jamieson ◽  
Suzanne Lemieux ◽  
...  
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Nk Cell ◽  
Class I ◽  
Inhibitory Receptor ◽  
Inhibitory Receptors ◽  
Mhc Molecules ◽  
Histocompatibility Complex ◽  
Mhc Class I Molecule ◽  
Self Tolerance

Abstract It is widely believed that self-tolerance of natural killer (NK) cells occurs because each NK cell expresses at least one inhibitory receptor specific for a host major histocompatibility complex (MHC) class I molecule. Here we report that some NK cells lack all known self-MHC–specific inhibitory receptors, yet are nevertheless self-tolerant. These NK cells exhibit a normal cell surface phenotype and some functional activity. However, they respond poorly to class I–deficient normal cells, tumor cells, or cross-linking of stimulatory receptors, suggesting that self-tolerance is established by dampening stimulatory signaling. Thus, self-tolerance of NK cells in normal animals can occur independently of MHC-mediated inhibition, and hyporesponsiveness plays a role in self-tolerance of NK cells, as also proposed for B and T cells.

scholarly journals Models for Natural Killer Cell Repertoire Formation

2003 ◽  
Vol 10 (2-4) ◽  
pp. 183-192 ◽  
Author(s):  
Mali Salmon-Divon ◽  
Petter Höglund ◽  
Ramit Mehr
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Mhc Class I ◽  
Killer Cell ◽  
Stable Expression ◽  
Class I ◽  
Inhibitory Receptors ◽  
Cell Repertoire ◽  
Class I Mhc ◽  
Mhc Molecules

Natural killer (NK) cells lyse only cells that do not express sufficient levels of self class I MHC molecules. Inhibition of lysis is mediated by inhibitory receptors expressed by NK cells, such as the murine Ly49 receptors, that bind to MHC class I molecules. Since inhibitory receptor genes and MHC class I genes are located on different chromosomes, and are hence not automatically co-inherited, NK cells apparently adapt to the MHC environment during their development. Two models have been proposed to account for this “education” process of NK cells. Thetwo-step selectionmodel postulates that developing NK cells initiate the stable expression of a random set of Ly49 genes, and then undergo two selection steps, one for cells that express a sufficient number of self-MHC receptors, and one against cells that express too many inhibitory receptors. Thesequentialmodel postulates that a cell keeps initiating the stable expression of additional inhibitory receptors until a sufficient expression level of self-MHC specific receptors is reached, and the cell matures. In this study we implement both models in computer simulations, and compare simulation results to experimental data, in order to evaluate the relative plausibility of the two models.

scholarly journals HLA upregulation during dengue virus infection suppresses the natural killer cell response

2019 ◽  
Author(s):  
Julia L. McKechnie ◽  
Davis Beltran ◽  
Arcelys Pitti ◽  
Lisseth Saenz ◽  
Ana B. Araúz ◽  
...  
Keyword(s):  
Dengue Virus ◽  
Nk Cells ◽  
Natural Killer ◽  
Cell Response ◽  
Nk Cell ◽  
Hla Class I ◽  
Denv Infection ◽  
Class I ◽  
Hla Class I Molecules

AbstractDengue virus (DENV) is the most prevalent mosquito-borne virus in the world and a major cause of morbidity in the tropics and subtropics. Upregulation of HLA class I molecules has long been considered a feature of DENV infection, yet this has not been evaluated in the setting of natural infection. Natural killer (NK) cells, an innate immune cell subset critical for mounting an early response to viral infection, are inhibited by self HLA class I, suggesting that upregulation of HLA class I during DENV infection could dampen the NK cell response. Here we addressed whether upregulation of HLA class I molecules occurs during in vivo DENV infection and, if so, whether this suppresses the NK cell response. We found that HLA class I expression was indeed upregulated during acute DENV infection across multiple cell lineages in vivo. To better understand the role of HLA class I upregulation, we infected primary human monocytes, a major target of DENV infection, in vitro. Upregulation of total HLA class I is dependent on active viral replication and is mediated in part by cytokines and other soluble factors induced by infection, while upregulation of HLA-E occurs in the presence of replication-incompetent virus. Importantly, blocking DENV-infected monocytes with a pan-HLA class I Fab nearly doubles the frequency of degranulating NK cells, while blocking HLA-E does not significantly improve the NK cell response. These findings demonstrate that upregulation of HLA class I during DENV infection suppresses the NK cell response, potentially contributing to disease pathogenesis.

scholarly journals Transgenic expression of the Ly49A natural killer cell receptor confers class I major histocompatibility complex (MHC)-specific inhibition and prevents bone marrow allograft rejection.

1996 ◽  
Vol 184 (5) ◽  
pp. 2037-2041 ◽  
Author(s):  
W Held ◽  
D Cado ◽  
D H Raulet
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Major Histocompatibility Complex ◽  
Nk Cells ◽  
Natural Killer ◽  
Nk Cell ◽  
Class I ◽  
Specific Inhibition ◽  
Transgenic Expression ◽  
Histocompatibility Complex

Natural killer (NK) cells and some T cells are endowed with receptors specific for class I major histocompatibility complex (MHC) molecules that can inhibit cellular effector functions. The function of the Ly49 receptor family has been studied in vitro, but no gene transfer experiments have directly established the role of these receptors in NK cell functions. We show here that transgenic expression of the H-2Dd-specific Ly49A receptor in all NK cells and T cells conferred class I-specific inhibition of NK cell-mediated target cell lysis as well as of T cell proliferation. Furthermore, transgene expression prevented NK cell-mediated rejection of allogeneic H-2d bone marrow grafts by irradiated mice. These results demonstrate the function and specificity of Ly49 receptors in vivo, and establish that their subset-specific expression is necessary for the discrimination of MHC-different cells by NK cells in unmanipulated mice.

scholarly journals Immunoreceptor tyrosine-based inhibitory motif–dependent functions of an MHC class I-specific NK cell receptor

2017 ◽  
Vol 114 (40) ◽  
pp. E8440-E8447 ◽  
Author(s):  
Michael D. Bern ◽  
Diana L. Beckman ◽  
Takashi Ebihara ◽  
Samantha M. Taffner ◽  
Jennifer Poursine-Laurent ◽  
...  
Keyword(s):  
Nk Cells ◽  
Mhc Class I ◽  
Nk Cell ◽  
Single Gene ◽  
Cell Receptor ◽  
Class I ◽  
Class I Mhc ◽  
Mhc I ◽  
Receptor Repertoire

Natural killer (NK) cells express MHC class I (MHC-I)-specific receptors, such as Ly49A, that inhibit killing of cells expressing self–MHC-I. Self–MHC-I also “licenses” NK cells to become responsive to activating stimuli and regulates the surface level of NK-cell inhibitory receptors. However, the mechanisms of action resulting from these interactions of the Ly49s with their MHC-I ligands, particularly in vivo, have been controversial. Definitive studies could be derived from mice with targeted mutations in inhibitory Ly49s, but there are inherent challenges in specifically altering a single gene within a multigene family. Herein, we generated a knock-in mouse with a targeted mutation in the immunoreceptor tyrosine-based inhibitory motif (ITIM) of Ly49A that abolished the inhibitory function of Ly49A in cytotoxicity assays. This mutant Ly49A caused a licensing defect in NK cells, but the surface expression of Ly49A was unaltered. Moreover, NK cells that expressed this mutant Ly49A exhibited an altered inhibitory receptor repertoire. These results demonstrate that Ly49A ITIM signaling is critical for NK-cell effector inhibition, licensing, and receptor repertoire development.

scholarly journals M144, a Murine Cytomegalovirus (Mcmv)-Encoded Major Histocompatibility Complex Class I Homologue, Confers Tumor Resistance to Natural Killer Cell–Mediated Rejection

1999 ◽  
Vol 190 (3) ◽  
pp. 435-444 ◽  
Author(s):  
Erika Cretney ◽  
Mariapia A. Degli-Esposti ◽  
Eloise H. Densley ◽  
Helen E. Farrell ◽  
Nick J. Davis-Poynter ◽  
...  
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Cell Line ◽  
Nk Cell ◽  
Effector Function ◽  
Class I ◽  
Murine Cytomegalovirus ◽  
Cell Effector Function ◽  
Cell Effector

Until now, it has been unclear whether murine cytomegalovirus (MCMV)-encoded protein m144 directly regulates natural killer (NK) cell effector function and whether the effects of m144 are only strictly evident in the context of MCMV infection. We have generated clones of the transporter associated with antigen processing (TAP)-2–deficient RMA-S T lymphoma cell line and its parent cell line, RMA, that stably express significant and equivalent levels of m144. In vivo NK cell–mediated rejection of RMA-S-m144 lymphomas was reduced compared with rejection of parental or mock-transfected RMA-S clones, indicating the ability of m144 to regulate NK cell–mediated responses in vivo. Significantly, the accumulation of NK cells in the peritoneum was reduced in mice challenged with RMA-S-m144, as was the lytic activity of NK cells recovered from the peritoneum. Expression of m144 on RMA-S cells also conferred resistance to cytotoxicity mediated in vitro by interleukin 2–activated adherent spleen NK cells. In summary, the data demonstrate that m144 confers some protection from NK cell effector function mediated in the absence of target cell class I expression, but that in vivo the major effect of m144 is to regulate NK cell accumulation and activation at the site of immune challenge.

scholarly journals Natural Killer Cell Tolerance in Mice with Mosaic Expression of Major Histocompatibility Complex Class I Transgene

1997 ◽  
Vol 186 (3) ◽  
pp. 353-364 ◽  
Author(s):  
Maria H. Johansson ◽  
Charles Bieberich ◽  
Gilbert Jay ◽  
Klas Kärre ◽  
Petter Höglund
Keyword(s):  
Major Histocompatibility Complex ◽  
Nk Cells ◽  
Natural Killer ◽  
Mhc Class I ◽  
Nk Cell ◽  
Class I ◽  
Cell Tolerance ◽  
Histocompatibility Complex ◽  
Missing Self

We have studied natural killer (NK) cell tolerance in a major histocompatibility complex (MHC) class I transgenic line, DL6, in which the transgene product was expressed on only a fraction of blood cells. In contrast with transgenic mice expressing the same transgene in all cells, NK cells from mosaic mice failed to reject transgene-negative bone marrow or lymphoma grafts. However, they retained the capability to reject cells with a total missing-self phenotype, i.e., cells lacking also wild-type MHC class I molecules. Tolerance against transgene-negative cells was demonstrated also in vitro, and could be broken if transgene-positive spleen cells of mosaic mice were separated from negative cells before, or after 4 d of culture in interleukin-2. The results provide support for selective NK cell tolerance to one particular missing-self phenotype but not to another. We suggest that this tolerance is determined by NK cell interactions with multiple cells in the environment, and that it is dominantly controlled by the presence of cells lacking a specific MHC class I ligand. Furthermore, the tolerant NK cells could be reactivated in vitro, which suggests that the tolerance occurs without deletion of the potentially autoreactive NK cell subset(s), and that it may be dependent upon the continuous presence of tolerizing cells.

scholarly journals Critical role for the Ly49 family of class I MHC receptors in adaptive natural killer cell responses

2018 ◽  
Vol 115 (45) ◽  
pp. 11579-11584 ◽  
Author(s):  
Andrew Wight ◽  
Ahmad Bakur Mahmoud ◽  
Michal Scur ◽  
Megan M. Tu ◽  
Mir Munir A. Rahim ◽  
...  
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Nk Cell ◽  
Critical Role ◽  
Killer Cell ◽  
Class I ◽  
Antigen Specificity ◽  
Cell Memory ◽  
Class I Mhc ◽  
Memory Response

Adaptive natural killer (NK) cell memory represents a new frontier in immunology. Work over the last decade has discovered and confirmed the existence of NK cells with antigen-specific memories, which had previously been considered a unique property of T and B cells. These findings have shown that antigen-specific NK cells gain their specificity without the use of RAG proteins, representing a novel mechanism for generating antigen specificity, but the details of this mechanism have remained a mystery. We have discovered that members of the Ly49 family of surface receptors are critically involved in both the sensitization and the challenge phases of an NK cell memory response, as is antigen presentation from their binding partner, the class I MHC. Moreover, we demonstrate that the Ly49-interacting component of a presented antigen dictates the specificity of the NK cell memory response, implicating Ly49 receptors themselves in antigen-specific recognition. Finally, we demonstrate that adaptive NK cell memories can protect against an otherwise lethal melanoma without T cell or B cell support. These findings offer insight into the mechanism behind NK cell antigen specificity and demonstrate the clinical potential of this adaptive immune cell.

scholarly journals Recruitment and Activation of Natural Killer (Nk) Cells in Vivo Determined by the Target Cell Phenotype

2000 ◽  
Vol 191 (1) ◽  
pp. 129-138 ◽  
Author(s):  
Rickard Glas ◽  
Lars Franksson ◽  
Clas Une ◽  
Maija-Leena Eloranta ◽  
Claes Öhlén ◽  
...  
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Tumor Cells ◽  
Mhc Class I ◽  
Nk Cell ◽  
Interferon Γ ◽  
Class I ◽  
Cell Phenotype ◽  
Target Cells

Natural killer (NK) cells can spontaneously lyse certain virally infected and transformed cells. However, early in immune responses NK cells are further activated and recruited to tissue sites where they perform effector functions. This process is dependent on cytokines, but it is unclear if it is regulated by NK cell recognition of susceptible target cells. We show here that infiltration of activated NK cells into the peritoneal cavity in response to tumor cells is controlled by the tumor major histocompatibility complex (MHC) class I phenotype. Tumor cells lacking appropriate MHC class I expression induced NK cell infiltration, cytotoxic activation, and induction of transcription of interferon γ in NK cells. The induction of these responses was inhibited by restoration of tumor cell MHC class I expression. The NK cells responding to MHC class I–deficient tumor cells were ∼10 times as active as endogenous NK cells on a per cell basis. Although these effector cells showed a typical NK specificity in that they preferentially killed MHC class I–deficient cells, this specificity was even more distinct during induction of the intraperitoneal response. Observations are discussed in relation to a possible adaptive component of the NK response, i.e., recruitment/activation in response to challenges that only NK cells are able to neutralize.

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.

Sign in / Sign up

Export Citation Format

Share Document