The Role of Ly49A and 5E6(Ly49C) Molecules in Hybrid Resistance Mediated by Murine Natural Killer Cells Against Normal T Cell Blasts

Yu, Yanbo; George, Thaddeus C.; Dorfman, Jeffrey R.; Roland, Jacques; Kumar, Vinay; Bennett, Michael V. L.

doi:10.1016/s1074-7613(00)80299-x

Cited by 209 publications

(172 citation statements)

References 40 publications

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“…In accordance with previous publications [20,28], 5E6 F(ab') 2 -mediated blocking of Ly49C/I inhibitory NK cell receptors resulted in enhanced killing of syngeneic RMA tumor cells and B6 lymphoblasts in an in vitro cytotoxicity assay (Fig. 1B).…”

Section: E6 F(ab') 2 Bind To Ly49c/i Receptors and Enhance Lysis Of supporting

confidence: 92%

“…The corresponding function in mice is mediated by Ly49 receptors, which belong to a family of dimeric type II integral membrane proteins with a C-type (calcium-dependent) lectin-like domain [16][17][18][19]. Relevant receptors for this study are the Ly49C and I receptors, which are expressed by 35-60% of NK cells in the C57BL/6 (B6) strain and bind to H-2K b ligands expressed in the B6 mouse, and the Ly49G2 receptor, binding to H-2D d and H-2L d but lacking ligands in the B6 mouse [17][18][19][20].…”

Section: Introductionmentioning

confidence: 99%

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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: E6 F(ab') 2 Bind To Ly49c/i Receptors and Enhance Lysis Of supporting

confidence: 92%

Section: Introductionmentioning

confidence: 99%

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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“…Collectively, Ly-49 molecules may contribute to a balance of positive and negative signals that control murine NK activities as well as those of certain subsets of T cells (3,7,8,9,18). Most studies of Ly-49 gene family members have used the B6 strain as a prototype.…”

Section: Predicted Amino Acid Sequences Of Ly-49a Ly-49d and Ly-49pmentioning

confidence: 99%

“…A number of inhibitory Ly-49 family members have been shown to recognize class I molecules as ligands, including Ly-49A, -C, and -G, in their apparent role of inhibiting NK cells unless there is reduction of self-MHC expression (7)(8)(9). Much less is understood regarding the ligand specificity and role of activating Ly-49 members.…”

Section: Mhc Dependence Of Ly-49p-stimulated Rnk-16 Lysis Of Con A-acmentioning

confidence: 99%

“…Multiple Ly-49 receptors can be expressed simultaneously by an individual NK cell (5,6). A number of Ly-49 family members recognize class I MHC molecules, including Ly-49A, -C, and -G, and serve to inhibit NK function (7)(8)(9). Inhibitory Ly-49 receptors, as with CD94/NKG2A and a variety of Ig domain-containing receptors, inhibit NK function by recruiting the SH2 domain-containing tyrosine phosphatase SHP-1 3 to disrupt tyrosine kinase-dependent, membrane-proximal, signaling events (10).…”

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confidence: 99%

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Ly-49P Activates NK-Mediated Lysis by Recognizing H-2Dd 1

Silver

Gong

Chang

et al. 2000

The Journal of Immunology

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Little is known regarding the ligand specificity of Ly-49 activating receptor subfamily members expressed by NK cells. A new Ly-49 activating receptor related to Ly-49A in its extracellular domain, designated Ly-49P, was recently cloned from 129 strain mice. We independently cloned an apparent allele of Ly-49P expressed by nonobese diabetic and nonobese diabetes-resistant mouse strain NK cells. We found it to be reactive with the A1 Ab thought to recognize a polymorphic epitope expressed only by the Ly-49A inhibitory receptor of the C57BL/6 strain. Rat RNK-16 cells transfected with Ly-49P mediated reverse Ab-dependent cellular cytotoxicity of FcR-positive target cells, indicating that Ly-49P can activate NK-mediated lysis. We determined that RNK-16 lysis of Con A blasts induced by Ly-49P was MHC dependent, resulting in efficient lysis of H-2Dd-bearing targets. We found that the Dd α1/α2 domain is required for Ly-49P-mediated RNK-16 activation, as determined by exon shuffling and transfection. Thus, Ly-49P is the second activating Ly-49 receptor demonstrated to induce NK cytotoxicity by recognizing a class I MHC molecule.

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β2 -Microglobulin-deficient NK cells show increased sensitivity to MHC class I-mediated inhibition, but self tolerance does not depend upon target cell expression of H-2Kb and Db heavy chains

et al. 1998

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Mice lacking g 2-microglobulin (g 2 m − mice) express greatly reduced levels of MHC class I molecules, and cells from g 2 m − mice are therefore highly sensitive to NK cells. However, NK cells from g 2 m − mice fail to kill g 2 m − normal cells, showing that they are self tolerant. In a first attempt to understand better the basis of this tolerance, we have analyzed more extensively the target cell specificity of g 2 m − NK cells. In a comparison between several MHC class I-deficient and positive target cell pairs for sensitivity to g 2 m − NK cells, we made the following observations: First, g 2 m − NK cells displayed a close to normal ability to kill a panel of MHC class I-deficient tumor cells, despite their nonresponsiveness to g 2 m − concanavalin A (Con A)-activated T cell blasts. Secondly, g 2 m − NK cells were highly sensitive to MHC class I-mediated inhibition, in fact more so than g 2 m + NK cells. Thirdly g 2 m − NK cells were not only tolerant to g 2 m − Con A blasts but also to Con A blasts from H-2K b− /D b− double deficient mice in vitro. We conclude that NK cell tolerance against MHC class I-deficient targets is restricted to nontransformed cells and independent of target cell expression of MHC class I free heavy chains. The enhanced ability of g 2 m − NK cells to distinguish between MHC class I-negative and-positive target cells may be explained by increased expression of Ly49 receptors, as described previously. However, the mechanisms for enhanced inhibition by MHC class I molecules appear to be unrelated to self tolerance in g 2 m − mice, which may instead operate through mechanisms involving triggering pathways. Abbreviations: I 2 m: g 2-Microglobulin TAP: Transporter associated with antigen processing

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The Role of Ly49A and 5E6(Ly49C) Molecules in Hybrid Resistance Mediated by Murine Natural Killer Cells Against Normal T Cell Blasts

Cited by 209 publications

References 40 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

Ly-49P Activates NK-Mediated Lysis by Recognizing H-2Dd 1

β2 -Microglobulin-deficient NK cells show increased sensitivity to MHC class I-mediated inhibition, but self tolerance does not depend upon target cell expression of H-2Kb and Db heavy chains

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