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 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 The requirement for NKG2D in NK cell–mediated rejection of parental bone marrow grafts is determined by MHC class I expressed by the graft recipient

Blood ◽  
2010 ◽  
Vol 116 (24) ◽  
pp. 5208-5216 ◽  
Author(s):  
Joshua N. Beilke ◽  
Jonathan Benjamin ◽  
Lewis L. Lanier
Keyword(s):  
Bone Marrow ◽  
Major Histocompatibility Complex ◽  
Nk Cells ◽  
Nk Cell ◽  
Class I ◽  
Major Histocompatibility ◽  
Major Histocompatibility Complex Haplotype ◽  
Histocompatibility Complex ◽  
Donor Cells ◽  
Graft Recipient

Abstract Natural killer (NK) cells provide a unique barrier to semiallogeneic bone marrow (BM) transplantation. In the setting where the parents donate to the F1 offspring, rejection of parental bone marrow occurs. This “hybrid resistance” is completely NK cell dependent, as T cells in the F1 recipient tolerate parental grafts. Previously, we demonstrated that rejection of BALB/c parental BM by (BALB/c × C57BL/6) F1-recipient NK cells is dependent on the NKG2D-activating receptor, whereas rejection of parental C57BL/6 BM does not require NKG2D. BALB/c and B6 mice possess different NKG2D ligand genes and express these ligands differently on reconstituting BM cells. Herein, we show that the requirement for NKG2D in rejection depends on the major histocompatibility complex haplotype of donor cells and not the differences in the expression of NKG2D ligands. NKG2D stimulation of NK cell–mediated rejection was required to overcome inhibition induced by H-2Dd when it engaged an inhibitory Ly49 receptor, whereas rejection of parental BM expressing the ligand, H-2Kb, did not require NKG2D. Thus, interactions between the inhibitory receptors on F1 NK cells and parental major histocompatibility complex class I ligands determine whether activation via NKG2D is required to achieve the threshold for rejection of parental BM grafts.

scholarly journals Acquisition of External Major Histocompatibility Complex Class I Molecules by Natural Killer Cells Expressing Inhibitory Ly49 Receptors

2001 ◽  
Vol 194 (10) ◽  
pp. 1519-1530 ◽  
Author(s):  
Anna Sjöström ◽  
Mikael Eriksson ◽  
Cristina Cerboni ◽  
Maria H. Johansson ◽  
Charles L. Sentman ◽  
...  
Keyword(s):  
Major Histocompatibility Complex ◽  
Nk Cells ◽  
Natural Killer ◽  
Mhc Class I ◽  
Nk Cell ◽  
Indirect Evidence ◽  
Class I ◽  
Target Cells ◽  
Major Histocompatibility ◽  
Histocompatibility Complex

Murine natural killer (NK) cells express inhibitory Ly49 receptors specific for major histocompatibility complex (MHC) class I molecules. We report that during interactions with cells in the environment, NK cells acquired MHC class I ligands from surrounding cells in a Ly49-specific fashion and displayed them at the cell surface. Ligand acquisition sometimes reached 20% of the MHC class I expression on surrounding cells, involved transfer of the entire MHC class I protein to the NK cell, and was independent of whether or not the NK cell expressed the MHC class I ligand itself. We also present indirect evidence for spontaneous MHC class I acquisition in vivo, as well as describe an in vitro coculture system with transfected cells in which the same phenomenon occurred. Functional studies in the latter model showed that uptake of H-2Dd by Ly49A+ NK cells was accompanied by a partial inactivation of cytotoxic activity in the NK cell, as tested against H-2Dd-negative target cells. In addition, ligand acquisition did not abrogate the ability of Ly49A+ NK cells to receive inhibitory signals from external H-2Dd molecules. This study is the first to describe ligand acquisition by NK cells, which parallels recently described phenomena in T and B cells.

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.

The Krüppel-Like Factor 4 (KLF4) Modulates Survival and Tissue Distribution of Natural Killer Cells.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 282-282
Author(s):  
Chun Shik Park ◽  
Ping-Hsien Lee ◽  
Takeshi Yamada ◽  
Maksim Mamonkin ◽  
H. Daniel Lacorazza
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Lymph Nodes ◽  
Nk Cells ◽  
Tissue Distribution ◽  
Natural Killer ◽  
Peripheral Blood ◽  
Nk Cell ◽  
Wild Type ◽  
Deficient Mice

Abstract Abstract 282 Natural Killer (NK) cells are important mediators of the innate immune system that could be targeted therapeutically to treat hematologic malignancies and to prevent graft-versus-host disease. Hence, a better understanding of NK cell survival and tissue trafficking at steady state is vital to develop cell-based therapies. Genes that control proliferation are often involved in tissue distribution of lymphocytes, such as KLF2 in T cells. KLF4, another member of the Krüppel-like factor family, can activate and repress genes involved in diverse cellular processes. We recently reported that KLF4 is part of a novel inhibitory pathway that prevents proliferation of naïve T cells during homeostasis and retain memory T cells in lymph nodes (Yamada et al., Nature Immunology, 2009). In this work, we studied the role of KLF4 in the development and maintenance of NK cells by deleting Klf4-floxed gene (fl/fl) using the Mx1-Cre system. The percentage of NK1.1+TCR- cells is significantly reduced in peripheral blood of Klf4-deficient (▪/▪) mice (fl/fl: 3.4±1.1 versus ▪/▪: 1.2±0.1, n=9) and also absolute numbers in spleen (▪/▪: 1.1±1.3 ×106, n=6) due to increased percentage of Annexin V positive cells (fl/fl: 9.2±3.2 versus ▪/▪: 22.9±15.5, n=15). The number of CD49d+TCR- cells was also significantly reduced in peripheral blood and spleen of Klf4-deficient mice. In contrast, the number of NK cells in bone marrow and lymph nodes of Klf4-deficient mice was similar to controls. Deletion of Klf4 gene led to reduced numbers of NK1.1+TCR-CD27+CD11b+ and NK1.1+TCR-CD27-CD11b+ cells, which correlated with increasing apoptosis of these subsets. Yet, the percentages of these NK cell subsets were normal in bone marrow ruling out a developmental defect in this tissue. Transplant of wild type and Klf4-deficient bone marrow cells into wild type mice suggested environmental rather than cell intrinsic defects. NK cells (NK1.1+TCR-) isolated from spleen of Klf4-deficient mice showed to be functional in a cytotoxicity assay using a mixture of differentially CFSE-labeled RMA-S (target) and EL4 (control). In summary, KLF4 plays a key role in the maintenance of mature NK cells in peripheral blood and spleen. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Protection from lysis by natural killer cells of group 1 and 2 specificity is mediated by residue 80 in human histocompatibility leukocyte antigen C alleles and also occurs with empty major histocompatibility complex molecules.

1996 ◽  
Vol 184 (3) ◽  
pp. 913-922 ◽  
Author(s):  
O Mandelboim ◽  
H T Reyburn ◽  
M Valés-Gómez ◽  
L Pazmany ◽  
M Colonna ◽  
...  
Keyword(s):  
Major Histocompatibility Complex ◽  
Nk Cells ◽  
Natural Killer ◽  
Target Cell ◽  
Nk Cell ◽  
Cell Lysis ◽  
Target Cells ◽  
Major Histocompatibility ◽  
Leukocyte Antigen ◽  
Histocompatibility Complex

Recognition of major histocompatibility complex class I molecules by natural killer (NR) cells leads to inhibition of target cell lysis. Based on the capacity of different human histocompatibility leukocyte antigen (HLA)-C and HLA-B molecules to inhibit target cell lysis by NK lines and clones, three NK allospecificities have been defined: NK1 and NK2 cells are inhibited by different HLA-C allotypes and NK3 cells by some HLA-B allotypes. The NK1 and NK2 inhibitory ligands on target cells correspond to a dimorphism of HLA-C at residues 77 and 80 in the alpha 1 helix: Asn77-Lys80 in NK1 and Ser77-Asn80 in NK2 inhibitory ligands. It has been reported that protection from NK1 killers depended on the presence of the Lys residue at position 80, an upward pointing residue near the end of the alpha 1 helix (and not on Asn77), whereas inhibition of NK2 effector cells required Ser77, a residue deep in the F pocket and interacting with the peptide (and not Asn80). As part of ongoing experiments to investigate the structural requirements for NK cell inhibition by HLA-C locus alleles, we also examined the effects of mutations at residues 77 and 80 on the ability of HLA-C alleles to confer protection from NK lysis. We present data confirming that the NK1 specificity depended on Lys80 (and not on Asn77); however recognition of NK2 ligands by NK cells was also controlled by the amino acid at position 80 (Asn), and mutation of Ser77 had no effect. Furthermore, bound peptide was shown to be unnecessary for the inhibition of NK cell-mediated lysis since HLA-C molecules assembled in the absence of peptide in RMA-S cells at 26 degrees C were fully competent to inhibit NK cells specifically. The implications of these data for peptide-independent recognition of HLA-C by NK receptors are discussed.

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