The Ly-49D Receptor Activates Murine Natural Killer Cells

Mason, Llewellyn H.; Anderson, Stephen; Yokoyama, Wayne M.; Smith, Hamish R.C.; Winkler‐Pickett, Robin; Ortaldo, John R.

doi:10.1084/jem.184.6.2119

Cited by 188 publications

(117 citation statements)

References 26 publications

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“…Fresh ex vivo spleen NK cells from NOD mice showed reactivity with 12A8, 4E5, 4D11 and 3D10 mAbs (Figure 1a), which in B6 mice indicate the presence of Ly49A, D, G and H/I. 20,27,28 However, no binding with Cwy-3 (Ly49G B6 ), AT8 (Ly49G BALB/129 ), 5E6 (Ly49C/I B6 ) or 14B11 (Ly49C/I/F/H B6 ) was detected (data not shown), possibly due to differences in allele epitopes or missing genes. Interestingly, the activating Ly49D receptor appears to be expressed on a majority of NOD NK cells as evidenced by mAb 4E5 staining of NK cells.…”

Section: Resultsmentioning

confidence: 99%

Ly49 cluster sequence analysis in a mouse model of diabetes: an expanded repertoire of activating receptors in the NOD genome

et al. 2008

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The mouse Ly49 and human killer cell immunoglobulin-like receptors (KIR) gene clusters encode activating and inhibitory class I MHC receptors on natural killer (NK) cells. A direct correlation between the presence of multiple activating KIR and various human autoimmune diseases including diabetes has been shown. Previous studies have implicated NK cell receptors in the development of diabetes in the non-obese diabetic (NOD) inbred mouse strain. To assess the contribution of Ly49 to NOD disease acceleration the Ly49 gene cluster of these mice was sequenced. Remarkably, the NOD Ly49 haplotype encodes the largest haplotype and the most functional activating Ly49 of any known mouse strain. These activating Ly49 include three Ly49p-related and two Ly49h-related genes. The NOD cluster contains large regions highly homologous to both C57BL/6 and 129 haplotypes, suggesting unequal crossing over as a mechanism of Ly49 haplotype evolution. Interestingly, the 129-like region has duplicated in the NOD genome. Thus, the NOD Ly49 cluster is a unique mix of elements seen in previously characterized Ly49 haplotypes resulting in a disproportionately large number of functional activating Ly49 genes. Finally, the functionality of activating Ly49 in NOD mice was confirmed in cytotoxicity assays.

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Section: Resultsmentioning

confidence: 99%

Ly49 cluster sequence analysis in a mouse model of diabetes: an expanded repertoire of activating receptors in the NOD genome

et al. 2008

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“…In addition to the inhibitory receptors of NK cells, there are members of the KIR, Ly49, and NKG2 families that lack ITIMs and generate activation signals rather than inhibitory signals (6,8). Examples include the short-tailed KIR such as KIR2DS2, Ly49D, H, L, M, P, and W and NKG2C (5, 6, 8 -10).…”

Section: N Atural Killer Cells Are Implicated In a Variety Of Immunementioning

confidence: 99%

“…Rat mAbs recognizing the various Ly49 family members, 4E5 (Ly49D), 12A8 (Ly49D/A), and 4D11 (Ly49G2) have been previously described (8,33,34). Similarly, anti-DAP12 antiserum (Rb20) has been described (16).…”

Section: Abs Nk Cells and Cell Linesmentioning

confidence: 99%

Aberrant DAP12 Signaling in the 129 Strain of Mice: Implications for the Analysis of Gene-Targeted Mice

McVicar

Winkler‐Pickett

Taylor

et al. 2002

The Journal of Immunology

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NK cells are implicated in antiviral responses, bone marrow transplantation and tumor immunosurveillance. Their function is controlled, in part, through the Ly49 family of class I binding receptors. Inhibitory Ly49s suppress signaling, while activating Ly49s (i.e., Ly49D) activate NK cells via the DAP12 signaling chain. Activating Ly49 signaling has been studied primarily in C57BL/6 mice, however, 129 substrains are commonly used in gene-targeting experiments. In this study, we show that in contrast to C57BL/6 NK cells, cross-linking of DAP12-coupled receptors in 129/J mice induces phosphorylation of DAP12 but not calcium mobilization or cytokine production. Consistent with poor-activating Ly49 function, 129/J mice reject bone marrow less efficiently than C57BL/6 mice. Sequence analysis of receptors and DAP12 suggests no structural basis for inactivity, and both the 129/J and C57BL/6 receptors demonstrate normal function in a reconstituted receptor system. Most importantly, reconstitution of Ly49D in 129/J NK cells demonstrated that the signaling deficit is within the NK cells themselves. These unexpected findings bring into question any NK analysis of 129/J, 129Sv, or gene-targeted mice derived from these strains before complete backcrossing, and provide a possible explanation for the differences observed in the immune response of 129 mice in a variety of models.

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“…The purity of the NK cultures was checked, and preparations with Ͼ95% of NK1.1 ϩ were used for the experiments. NKmediated cytotoxicity was quantified using 51 Cr-labeled target cells according to established protocols (31).…”

Section: Nk Cell Preparation and Cytotoxicity Assaysmentioning

confidence: 99%

Differential and Nonredundant Roles of Phospholipase Cγ2 and Phospholipase Cγ1 in the Terminal Maturation of NK Cells

Regunathan

Chen

Kutlesa

et al. 2006

The Journal of Immunology

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NK cells play a central role in mediating innate immune responses. Activation of NK cells results in cytotoxicity, cytokine, and chemokine secretions. In this study, we show that in mice with targeted deletion of phospholipase Cγ (PLCγ)2, one of the key signal transducers, there are profound effects on the development and terminal maturation of NK cells. Lack of PLCγ2 significantly impaired the ability of lineage-committed NK precursor cells to acquire subset-specific Ly49 receptors and thereby terminal maturation of NK cells. Overexpression of isozyme, PLCγ1, in PLCγ2-deficient NK cells resulted in the successful Ly49 acquisition and terminal maturation of the NK cells; however, it could only partially rescue NKG2D-mediated cytotoxicity with no cytokine production. Furthermore, PLCγ2-deficient NK cells failed to mediate antitumor cytotoxicity and inflammatory cytokine production, displaying a generalized hyporesponsiveness. Our results strongly demonstrate that PLCγ1 and PLCγ2 play nonredundant and obligatory roles in NK cell ontogeny and in its effector functions.

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The Ly-49D Receptor Activates Murine Natural Killer Cells

Cited by 188 publications

References 26 publications

Ly49 cluster sequence analysis in a mouse model of diabetes: an expanded repertoire of activating receptors in the NOD genome

Ly49 cluster sequence analysis in a mouse model of diabetes: an expanded repertoire of activating receptors in the NOD genome

Aberrant DAP12 Signaling in the 129 Strain of Mice: Implications for the Analysis of Gene-Targeted Mice

Differential and Nonredundant Roles of Phospholipase Cγ2 and Phospholipase Cγ1 in the Terminal Maturation of NK Cells

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