Murine<i>Nkg2d</i>and<i>Cd94</i>are clustered within the natural killer complex and are expressed independently in natural killer cells

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.

Section: Role Of Plc␥2 In the Downstream Activation Of Nkg2d Receptormentioning

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

“…Whereas CD94/NKG2A orthologs are clearly present in both species (3)(4)(5), it is not yet clear whether true orthologs of mouse Ly-49 and human KIR exist in the reciprocal species. Although an incomplete human Ly49 has been isolated (6), functional human Ly-49 molecules have yet to be described.…”

mentioning

confidence: 99%

Inducible Expression of the gp49B Inhibitory Receptor on NK Cells

Wang

Chu

Dokun

et al. 2000

Self Cite

Murine NK cells express inhibitory receptors belonging to the C-type lectin-like (Ly-49, CD94/NKG2) and Ig superfamily-related (gp49) receptors. The murine gp49B receptor displays structural homology with human killer inhibitory receptors, and was previously identified to be a receptor on mast cells and activated NK cells. The gp49B receptor is highly related to gp49A, a receptor with unknown function. In this study, using a novel mAb produced against soluble gp49B molecules that cross-reacts with gp49A, we examined the cellular distribution and function of these receptors. gp49 is constitutively expressed on cells of the myeloid lineage throughout development, as well as on mature cells. Importantly, gp49 is not expressed on spleen- and liver-derived lymphocytes, including NK cells, but its expression is induced in vitro on NK cells following IL-2 stimulation, or in vivo by infection with murine CMV. Molecular studies revealed that both the immunoreceptor tyrosine-based inhibitory motif-containing gp49B as well as immunoreceptor tyrosine-based inhibitory motif-less gp49A receptors are up-regulated on NK cells following murine CMV infection. When co-cross-linked with NK1.1, gp49B can inhibit NK1.1-mediated cytokine release by NK cells. Taken together, these studies demonstrate that the expression of gp49B on NK cells is regulated, providing the first example of an in vivo activation-induced NK cell inhibitory receptor, in contrast to the constitutively expressed Ly49 family.

“…Another group of NK cell MHC class I receptors is characterized by disulfide-linked dimer of type II transmembrane protein with an extracellular region homologous to carbohydrate recognition domain of C-type lectin. This group includes the Ly49 family in mice (9 -12) and rats (13) and CD94/NKG2 heterodimer found in humans (14) and rodents (15,16).…”

mentioning

confidence: 99%

The NK Cell MHC Class I Receptor Ly49A Detects Mutations on H-2Dd Inside and Outside of the Peptide Binding Groove

Matsumoto

Yokoyama

Kojima

et al. 2001

Self Cite

N atural killer cells are a group of lymphocytes that spontaneously lyse certain tumor targets (1). The finding that cell lines defective for MHC class I expression were efficiently lysed by NK cells led to the missing self hypothesis: NK cells kill cells that lack normal expression of MHC class I molecules (2). Recent studies have established that NK cells express inhibitory receptors for MHC class I molecules (3, 4). The receptors can be classified into two groups by their structural characteristics. One group that includes human killer cell Ig-like receptors is characterized by two or three Ig-like domains in the extracellular region and configuration of type I transmembrane proteins (5, 6). NK cell MHC class I receptors of Ig-type have thus far been found only in primates, but not in rodents. gp49B1, which belongs to the Ig superfamily, is expressed on mouse NK cells (7,8); however, the ligand for gp49B1 may not be MHC class I. Another group of NK cell MHC class I receptors is characterized by disulfide-linked dimer of type II transmembrane protein with an extracellular region homologous to carbohydrate recognition domain of C-type lectin. This group includes the Ly49 family in mice (9 -12) and rats (13) and CD94/NKG2 heterodimer found in humans (14) and rodents (15, 16).The inhibitory receptors of both groups have one or two immune receptor tyrosine-based inhibitory motifs (ITIM) 3 characterized by an IXYXXL sequence in the cytoplasmic region (17). Upon ligand recognition, the Tyr residue in the ITIM is phosphorylated and recruits the Src homology domain-containing protein tyrosine phosphatase 1 with Src homology 2 domains. The recruited Src homology domain-containing protein tyrosine phosphatase 1 is believed to dephosphorylate unknown critical substrates to shut down positive signaling. There are activating type of MHC class I receptors of C-type lectin and Ig-type with extracellular domains similar to those of the inhibitory receptors. Instead of cytoplasmic ITIM, the activating receptors have characteristic charged amino acid residues in the transmembrane region, and by that associate with DAP12, an adapter component with cytoplasmic immune receptor tyrosine-based activating motif (18). Engagement of such receptors initiates an activation signaling cascade analogous to T or B cell receptor signaling.Mouse NK cells express the Ly49 family of receptors, which includes Ͼ10 members (9 -12, 19). Several lines of evidence demonstrate that Ly49A, a primary member of Ly49 family, is an inhibitory receptor that specifically recognizes a conformational epitope on H- The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.