Regulation of NK Cell Function by Major Histocompatibility Complex (MHC) Class I Restricted Receptors
In contrast to T cells, NK cells kill a broad array of targets in a human leukocyte antigen (HLA)-unrestricted manner. However, recent observations counter the notion that NK killing is totally MHC-unrestricted. While antigen recognition presented by MHC class I molecules activates T cells, class I antigen presentation can render targets resistant to lysis by NK cells. Thus, NK cell receptor function may be activating and/or inhibitory (figure 1). As originally proposed by Ljunggren and Kärre19 in the “missing self ” hypothesis, it is now well recognized that class I downregulation by transformation or infection may make cells susceptible to NK cell lysis.20,21 Class I-recognizing NK receptors were identified first in the mouse as the Ly49 proteins, which are type II lectins capable of binding sugar moieties on class I molecules.22 Although a truncated nonfunctional Ly49L has been found in man, humans do not use Ly49 receptors.23 In contrast, human class I-recognizing NK cell receptors are type I membrane glycoproteins and members of the immunoglobulin superfamily that are not present in mice.24,25 Although thought initially to represent a paradox, it is now known that human NK cells express both immunoglobulin and lectin-type receptors.26–28
Chromosome 19 is a hot spot for NK cell receptors defined by immunoglobulin structural moieties. Hence, they are termed killer immunoglobulin-like receptors (KIR). The individual receptor names are assigned by the number of corresponding immunoglobulin domains (e.g., KIR2D, KIR3D) and by the length of their associated cytoplasmic tail, either long (L) or short (S) (e.g., KIR2DL, KIR2DS1).29–31 A KIR can signal inhibition or activation when class I MHC is recognized based on the length of its cytoplasmic tail. Long cytoplasmic tails contain immunoreceptor tyrosine-based inhibitory motifs that signal inhibition when the KIR is appropriately ligated. At least three of these inhibitory receptors (KIR2DL1, KIR2DL2, KIR3DL1) have class I ligands identified (cw4, cw3, bw4). KIR with short cytoplasmic tails non-covalently associates with cytoplasmic DAP12 molecules that signal activation when the KIR is ligated. DAP12 is a disulfide-bonded homodimer containing an immunoreceptor tyrosine-based activation motif and its gene is also found on chromosome 19.32,33 The function of inhibitory KIR is summarized in figure 2.