The Host NK Cell Receptors of MHC Class I

The primary effector mechanisms [11,44,60,78] of NK cells are cell-mediated cytotoxicity and cytokine (in particular IFNy) secretion [11, 44, 68, 78]. For target recognition, NK cells express multiple germ line-encoded cell surface activating or inhibitory receptors, which provide a fine balance of signals governing NK cell function and serve as detectors of abnormal cells [60]. NK cell inhibitory receptors survey tissues for expression of MHC class I molecules, which under normal conditions are ubiquitously expressed. When MHC class I molecules are downregulated, as a consequence of transformation or viral infection, this inhibitory signal is absent, potentially resulting in destruction of infected target cells [53]. It has been proposed that this is a result of target cells expressing ligands that can engage one or more of the NK activating receptors [60], as seems to be the case during MCMV infection. MHC class I-like molecules can also regulate the NK cell response. In mice there are at least three receptor systems, namely, CD94/NKG2, NKG2D, and Ly49 [113], that recognize MHC class I or MHC class I-like molecules, which may participate in the recognition of the MCMV-infected cell and determine the host's response to infection (Fig. 2a). These receptors are all type II transmembrane-spanning C-type lectin-like glycoproteins, encoded by a family of related genes in a region known as the NK cell receptor gene complex (NKC), including the Cd94/Nkg2a, c-e, Nkg2d, and Ly49 genes (Fig. 2b). The NKC is located on the distal region of mouse chromosome 6, which is syntenic with regions on rat chromosome 4 andhuman chromosome 12p13 [60,113] (Fig. 2a). In contrast to the rodent species, the Ly49 gene cluster is absent in humans (a single copy of the Ly49L pseudogene has been identified in the human genome) [107]. Ly49 receptors are the functional analogs of human KIRs, which are encoded by genes located on human chromosome 19q26 [79]. Ly49 and KIR provide the largest genetic and functional diversity to the mouse and human NK cell receptor repertoires.

Mhc Class Related Chain

Fig. 2 Mouse C-type lectin-like MHC class I NK cell receptors map to distal chromosome 6. a Chromosomal and physical map of the distal portion of the NKC encoding showing the clustering of Cd94, Nkg2, and Ly49 genes. b Schematic representation of C-type lectin-like MHC class I receptors. As discussed in the text, receptors are heterodimers (CD94/NKG2A) or homodimers (NKG2D or Ly49). Inhibitory receptors have immunoreceptor tyrosine-based inhibitory motifs (ITIMs) in their cytoplasmic tail, which are capable of recruiting SHP-1 phosphatase to initiate the attenuation of intracellular signals. Activating receptors lack cytoplasmic ITIMs but contain an arginine residue in their transmembrane domain, which mediates their association with DAP12, a signaling protein containing a single immunoreceptor tyrosine-based activation motif (ITAM). In mice, NKG2D can associate either with DAP12 or DAP10 (an adapter protein capable of recruiting the p85 subunit of PI3 kinase)

Fig. 2 Mouse C-type lectin-like MHC class I NK cell receptors map to distal chromosome 6. a Chromosomal and physical map of the distal portion of the NKC encoding showing the clustering of Cd94, Nkg2, and Ly49 genes. b Schematic representation of C-type lectin-like MHC class I receptors. As discussed in the text, receptors are heterodimers (CD94/NKG2A) or homodimers (NKG2D or Ly49). Inhibitory receptors have immunoreceptor tyrosine-based inhibitory motifs (ITIMs) in their cytoplasmic tail, which are capable of recruiting SHP-1 phosphatase to initiate the attenuation of intracellular signals. Activating receptors lack cytoplasmic ITIMs but contain an arginine residue in their transmembrane domain, which mediates their association with DAP12, a signaling protein containing a single immunoreceptor tyrosine-based activation motif (ITAM). In mice, NKG2D can associate either with DAP12 or DAP10 (an adapter protein capable of recruiting the p85 subunit of PI3 kinase)

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