Follow the Leader: NK Cell Receptors for Classical and Nonclassical MHC Class I

and KIR3D molecules are heterogeneous. Isoforms with long cytoplasmic tails (i.e., KIR2DL and KIR3DL) contain ITIM that bind SHP-1 and inactivate NK cells. KIRs with short cytoplasmic domains (KIR2DS and KIR3DS) lack ITIM, but possess charged amino acids in their trans-membrane segments that permit association with DAP12, a membrane receptor expressing an immunoreceptor tyrosine-based activation motif (ITAM), that provides for Natural killer (NK) cells participate in the innate immune NK cell activation (Lanier et al., 1998). While the HLA response against certain viruses, intracellular bacteria, class I specificity of certain KIR isoforms remains un-parasites, and transformed cells (reviewed by Trinchieri, known or controversial, there is consensus that the 1989). Unlike B cells and T cells, NK cells do not express KIR2DL1 and KIR2DL2 molecules recognize a poly-immunoglobulins or T cell antigen receptors, and until morphism of HLA-C that maps to amino acids 77 and recently there was little insight into how these cells dis-80 in the HLA-C heavy chain (Figure 1). Amino acid 44 criminate self from nonself. The first clue about the work-in the first Ig-domain of KIR2DL1 and KIR2DL2 dic-ings of NK cells came from the observation that NK cells tates recognition of this HLA-C polymorphism. Similarly, preferentially kill cells lacking major histocompatibility KIR3DL1 recognizes a polymorphism in the ␣1 domain complex (MHC) class I on the cell surface. Based on of the HLA-B heavy chain in a region defining the Bw4 this observation, Kä rre and colleagues (Ljunggren and serological epitope (Figure 1). Both KIR2D and KIR3D Kä rre, 1990) proposed that NK cells recognize and elimi-molecules bind to HLA class I trimers, composed of nate cells that are " missing self. " As predicted, NK cells a class I heavy chain, ␤2-microglobulin, and a bound have been shown to express receptors for MHC class peptide. The class I–bound peptide can influence KIR I that upon ligation inhibit NK cell-mediated cytotoxicity recognition, but there is no obvious distinction between and cytokine secretion (reviewed by Lanier, 1997). While " self " versus foreign peptides. The structure of a KIR2D it is still uncertain what initiates the activation of NK cells protein has been solved, and it is similar to the family against virus-infected or transformed cells, the process of hematopoietic growth factor receptors (Fan et al., whereby expression of MHC class I on the antigen-1997). Like the Ly49 receptors, different KIR molecules presenting cell negatively regulates NK cell …