Allorecognition by murine natural killer cells: lysis of T‐lymphoblasts and rejection of bone‐marrow grafts

George, Thaddeus C.; Yu, Yanbo; Liu, Jingxuan; Davenport, Colleen; Lemieux, Suzanne; Stoneman, Earl; Mathew, Porunelloor A.; Kumar, Vinay; Bennett, Michael

doi:10.1111/j.1600-065x.1997.tb00937.x

Cited by 58 publications

(30 citation statements)

References 52 publications

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“…Although normal, resting spleen cells were not rejected upon Ly49C/I blockade other cell types may be more sensitive. Allogeneic and MHC-deficient BM cells can be rejected by NK cells [33,34] and activated T cells may express ligands for activating NK receptors and be more sensitive to NK-mediated lysis [32]. In our system, however, inhibitory receptor blockade did not induce rejection of CFSE-labeled syngeneic BM cells or Con A-activated T cells (Fig.…”

Section: Robust Self-tolerance After Ly49c/i Receptor Blockade In Vivomentioning

confidence: 64%

In vivo tumor cell rejection induced by NK cell inhibitory receptor blockade: Maintained tolerance to normal cells even in the presence of IL‐2

et al. 2010

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Missing-self-reactivity can be mimicked by blocking self-specific inhibitory receptors on NK cells, leading to increased rejection of syngeneic tumor cells. Using a mouse model, we investigated whether Ab-mediated blocking of inhibitory receptors, to a degree where NK cells rejected syngeneic tumor cells, would still allow self-tolerance toward normal syngeneic cells. Ly49C/I inhibitory receptors on C57BL/6 (H-2 b ) NK cells were blocked with F(ab') 2 fragments of the mAb 5E6. Inhibitory receptor blockade in vivo caused rejection of i.v. inoculated fluorescence-labeled syngeneic lymphoma line cells but not of syngeneic spleen cells, BM cells or lymphoblasts. The selective rejection of tumor cells was NK celldependent and specifically induced by Ly49C/I blockade. Moreover, selective tumor rejection was maintained after treatment with 5E6 F(ab') 2 for 9 wk, arguing against the induction of NK cell anergy or autoreactivity during this time. Combination therapy using 5E6 F(ab') 2 together with high dose IL-2 treatment further increased lymphoma cell rejection. In addition, combination therapy reduced growth of melanoma cell line tumors established by s.c. inoculation 3 days before start of treatment. Our results demonstrate that inhibitory receptor blockade does not result in attack on normal cells, despite potent reactivity against MHC class I-expressing tumors.

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Section: Robust Self-tolerance After Ly49c/i Receptor Blockade In Vivomentioning

confidence: 64%

In vivo tumor cell rejection induced by NK cell inhibitory receptor blockade: Maintained tolerance to normal cells even in the presence of IL‐2

et al. 2010

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“…This represents one of only a few instances in which the results of bone marrow graft rejection is not reflected by its in vitro correlate (35,36). It has been suggested that the rejection of bone marrow grafts does not depend on the cytotoxic function of NK cells (37).…”

Section: Discussionmentioning

confidence: 99%

Impaired Natural Killing of MHC Class I-Deficient Targets by NK Cells Expressing a Catalytically Inactive Form of SHP-1

Lowin-Kropf

Kunz

Beermann³

et al. 2000

The Journal of Immunology

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NK cell function is negatively regulated by MHC class I-specific inhibitory receptors. Transduction of the inhibitory signal involves protein tyrosine phosphatases such as SHP-1 (SH2-containing protein tyrosine phosphatase-1). To investigate the role of SHP-1 for NK cell development and function, we generated mice expressing a catalytically inactive, dominant-negative mutant of SHP-1 (dnSHP-1). In this paper we show that expression of dnSHP-1 does not affect the generation of NK cells even though MHC receptor-mediated inhibition is partially impaired. Despite this defect, these NK cells do not kill syngeneic, normal target cells. In fact dnSHP-1-expressing NK cells are hyporesponsive toward MHC-deficient target cells, suggesting that non-MHC-specific NK cell activation is significantly reduced. In contrast, these NK cells mediate Ab-dependent cell-mediated cytotoxicity and prevent the engraftment with β2-microglobulin-deficient bone marrow cells. A similar NK cell phenotype is observed in viable motheaten (mev) mice, which show reduced SHP-1 activity due to a mutation in the Shp-1 gene. In addition, NK cells in both mouse strains show a tendency to express more inhibitory MHC-specific Ly49 receptors. Our results demonstrate the importance of SHP-1 for the generation of functional NK cells, which are able to react efficiently to the absence of MHC class I molecules from normal target cells. Therefore, SHP-1 may play an as-yet-unrecognized role in some NK cell activation pathways. Alternatively, a reduced capacity to transduce SHP-1-dependent inhibitory signals during NK cell development may be compensated by the down-modulation of NK cell triggering pathways.

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“…In vivo, Ly49A binds to D d and D k (3)(4)(5) (3). Functional in vitro studies have suggested that Ly49I transmits an inhibitory signal from H2 b , but not from H2 d (9). However, until the mAb 8H7, which binds Ly49I but not Ly49C, was developed, one could not be sure of the function of this NK cell subset.…”

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confidence: 95%

Ly49I NK Cell Receptor Transgene Inhibition of Rejection of H2b Mouse Bone Marrow Transplants

Liu

Morris

Nguyen

et al. 2000

The Journal of Immunology

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The Ly49 family of genes encode NK cell receptors that bind class I MHC Ags and transmit negative signals if the cytoplasmic domains have immunoregulatory tyrosine-based inhibitory motifs (ITIMs). 5E6 mAbs recognize Ly49C and Ly49I receptors and depletion of 5E6+ NK cells prevents rejection of allogeneic or parental-strain H2d bone marrow cell (BMC) grafts. To determine the function of the Ly49I gene in the rejection of BMC grafts, we transfected fertilized eggs of FVB mice with a vector containing DNA for B6 strain Ly49I (Ly49IB6). Ly49IB6 is ITIM+ and is recognized by 5E6 as well as Ly49I-specific 8H7 mAbs. Normal FVB H2q mice reject H2b but not H2d BMC allografts, and the rejection of H2b BMC was inhibited partially by anti-NK1.1 and completely by anti-asialo GM1, but not by anti-CD8, Abs. In FVB mice, NK1.1 is expressed on only 60% NK cells. FVB.Ly49IB6 hosts failed to reject H2d or H2b BMC, but did reject class I-deficient TAP-1−/− BMC, indicating that NK cells were functional. Nondepleting doses of anti-Ly49I Abs reversed the acceptance of H2b BMC by FVB.Ly49IB6 mice. FVB.Ly49IB6+/− mice were crossed and back-crossed with 129 mice—H2b, 5E6−, poor responders to H2d BMC grafts. While transgene-negative H2b/q F1 or first-generation back-crossed mice rejected H2b marrow grafts (hybrid resistance), transgene-positive mice did not. Thus B6 strain Ly49I receptors transmit inhibitory signals from H2b MHC class I molecules. Moreover, Ly49IB6 has no positive influence on the rejection of H2d allografts.

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Allorecognition by murine natural killer cells: lysis of T‐lymphoblasts and rejection of bone‐marrow grafts

Cited by 58 publications

References 52 publications

In vivo tumor cell rejection induced by NK cell inhibitory receptor blockade: Maintained tolerance to normal cells even in the presence of IL‐2

In vivo tumor cell rejection induced by NK cell inhibitory receptor blockade: Maintained tolerance to normal cells even in the presence of IL‐2

Impaired Natural Killing of MHC Class I-Deficient Targets by NK Cells Expressing a Catalytically Inactive Form of SHP-1

Ly49I NK Cell Receptor Transgene Inhibition of Rejection of H2b Mouse Bone Marrow Transplants

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