SummaryNatural killer cells express clonally distributed receptors specific for major histocompatibility complex class I molecules. The human leukocyte antigen (HLA)-C-specific receptors have been molecularly identified and cloned. They exist not only as inhibitory (p58) but also as activatory (1050) receptors. Here we show that p50 and p58 are highly homologous in their extracellular regions formed by two Ig-like domains. In contrast, major differences exist in their transmembrane and cytoplasmic portions. Whereas p58 displays a 76-84-amino acid cytoplasmic tail containing an unusual antigen receptor activation motif, p50 is characterized by a shorter 39-amino acid tail. In addition, whereas p58 has a nonpolar transmembrane portion, p50 contains the charged amino acid Lys. These data strongly suggest that receptors with identical HLA-C allele specificity can mediate functions of opposite sign owing to their different transmembrane/cytoplasmic portions.T he cytolytic activity of NK cells is regulated by several clonally distributed inhibitory receptors specific for different groups of HLA class I andes. Interaction between these NK receptors and HLA class I molecules leads to inhibition of the NK-mediated target cell lysis (1--4). The receptors specific for two distinct groups of HLA-C alleles have been molecularly identified as p58 molecules, which react with either GL183 (5) or EB6 mAb (6). p58-encoding genes have recently been isolated and cloned (7). They encode for type 1 transmembrane proteins, which belong to the Ig supeffamily. They are characterized by two extracellular Ig-hke domains and display a high level of sequence homology. Recently, additional 50-kD molecular forms of EB6 or GL183 mAb-reactive receptors have been identified. They display the same HLA-C allele specificity of the corresponding p58 receptors but mediate NK cell triggering rather than inhibition (8). p50 receptors were found to be expressed only in some donors and to display a clonal distribution. Importantly, single NK cells did not coexpress p58 and p50 receptors with an identical HLA-C specificity (8). The protein backbone of p58 or p50 molecules has been shown to be 42 and 36 kD, respectively, after deglycosylation. These data, together with identical HLA-C specificity and mAb reactivity, suggested that p58 and p50 could be homologous in their extracellular domains but different in their intracellular portions. Cloning of several p58-homologous genes revealed the existence of molecules displaying cytoplasmic tails of different length. Here we show that, different from p58, the activatory p50 receptors are characterized by a short intracytoplasmic tail associated with a transmembrane portion containing a polar residue. Materials and Methods Isolation of EB6 + or GL183 § NK Clones and Definition of theFunction of their Receptors. EB6 § or GL183 § NK cell clones were isolated as previously described (4). Screening of clones for the expression of triggering (p50) or inhibitory (p58) receptors was performed by cytolytic tests using P...

Human Natural Killer Receptors and Their Ligands (Roberto Biassoni and Cristina Bottino, Istituto Nazionale per la Ricerca sul Cancro, Genova, Italy; Claudia Cantoni, Universita degli Studi di Genova, Istituto Giannina Gaslini, Genova, Italy; Alessandro Moretta, Universita degli Studi di Genova, Genova, Italy). Natural killer (NK) cells are a lymphocyte subpopulation that are important effectors of innate immune responses against infectious pathogens. They are thought to play an important role in host defense, not only against virally infected cells, but also in killing of tumor cells. Recent progress indicates that NK cells express an array of receptors, some of them clonally distributed, able to modulate the natural cytotoxicity. Three NK-specific activating receptors have been characterized; they belong to a novel receptor family called natural cytotoxicity receptors (NCR) and are represented by NKp46, NKp44, and NKp30. These receptors, upon engagement by their specific ligands, induce a strong activation of NK-mediated cytotoxic activity. This overview discusses the receptors (both activating and inhibitory) expressed by NK cells and their ligands. Finally, the dysfunction of one of these molecules occurring in a genetically inherited immunodeficiency is discussed.

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While 2B4 is a well‐known surface receptor involved in NK cell triggering and induction of cytotoxicity against CD48‐positive target cells, little is known about the downstream events which lead to NK cell activation. In this study we show that, in normal human NK cells, 2B4 constitutively associates with the linker for activation of T cells (LAT). Antibody‐mediated engagement of 2B4 resulted in tyrosine phosphorylation not only of 2B4 but also of the associated LAT molecules. Moreover, tyrosine phosphorylation of LAT led to the recruitment of intracytoplasmic signaling molecules including phospholipase Cγ and Grb2. These data support the concept that 2B4 may mediate NK cell triggering via a LAT‐dependent signaling pathway.