Nk Cell Recognition Of

NK cells are lymphocytes of the innate immune system that function early to control infections and have the ability to kill certain tumor cells.3,39 Lysis by NK cells is inversely related to target cell expression of class I MHC molecules. Since a number of viruses and tumor cells down regulate expression of class I molecules to avoid killing by cytotoxic T cells, NK cells are able to counter this adaptation. At the same time, the expression of class I molecules by healthy cells prevents their killing by NK cells. The inhibition of lysis is mediated by a set of NK-cell receptors specific for class I molecules. Among these are CD94/NKG2A, which recognize a subset of HLA class I leader peptides bound by the nonclas-

sic HLA-E molecule40 and certain killer immunoglobu-lin-like receptors (KIR) (Table 93.1). Inhibitory receptors KIR2DL1, KIR2DL2, KIR2DL3 recognize an HLA-Cw amino acid motif dimorphism at positions 77 and 80,41-44 the latter having been shown to be a receptor contact residue in crystallographic studies.43,44 KIR3DL1 is specific for the HLA-Bw4 epitope of a subset of HLA-B molecules.45 The Bw4 epitope is determined by amino acids in the region of 77 to 83 of the HLA heavy chain. KIR3DL2 has been indicated to be specific for HLA-A3 and -A11.46,47 Studies have indicated that KIR recognition of HLA is dependent on bound peptides, but there is little indication that the peptide contributes to the specificity of the interaction.3

In the normal autologous setting, all NK cells have at least one inhibitory receptor that interacts with an autologous HLA class I molecule, thus preventing attack against normal cells. In an HLA class I mismatched transplant there may be donor NK clones that are able to attack recipient cells because the class I ligands for the inhibitory receptors are not present on these cells. It has been indicated that these cells can mediate an effective GVL effect in HLA-mismatched transplants.48-50

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