In Section 3-26, we introduced the killer cell immunoglobulin-like receptors (KIRs) expressed by NK cells. Members of the KIRs recognize the classical class Ia MHC molecules HLA-A, -B, and -C, which present a diverse repertoire of peptides to CD8 T cells. Although KIRs interact with the same face of the MHC class I molecule as do T-cell receptors, the KIRs bind only at one end, and not over the whole area recognized by the T-cell receptor. Like MHC molecules, KIRs themselves are highly polymorphic, and they have undergone rapid evolution in humans. Only a few HLA-A and HLA-B alleles code for proteins that bind KIRs, but all HLA-C alleles express proteins that bind KIRs, indicating a specialization of HLA-C for regulating NK cells in humans.
Two other MHC class Ib molecules, HLA-F and HLA-G (see Fig. 6.26), can also inhibit cell killing by NK cells. HLA-G is expressed on fetus-derived placental cells that migrate into the uterine wall. These cells express no classical MHC class I molecules and cannot be recognized by CD8 T cells but, unlike other cells lacking such proteins, they are not killed by NK cells. This seems to be because HLA-G is recognized by another inhibitory receptor on NK cells, the leukocyte immunoglobulin-like receptor subfamily B member 1 (LILRB1), also called ILT-2 or LIR-1, which prevents the NK cell from killing the placental cells. HLA-F is expressed in a variety of tissues, although it is usually not detected at the cell surface except, for example, on some monocyte cell lines or on virus-transformed lymphoid cells. HLA-F is also thought to interact with LILRB1.
6-18 Members of the CD1 family of MHC class I-like molecules present microbial lipids to invariant NKT cells.
Some MHC class I-like genes map outside the MHC region. One small family of such genes is called CD1 and is expressed on dendritic cells, monocytes, and some thymocytes. Humans have five CD1 genes, CD1a through e, whereas mice express only two highly homologous versions of CD1d, namely, CD1d1 and CD1d2. CD1 proteins can present antigens to T cells, but they have two features that distinguish them from classical MHC class I molecules. The first is that CD1, although similar to an MHC class I molecule in its subunit organization and association with β2-microglobulin, behaves like an MHC class II molecule. It is not retained within the endoplasmic reticulum by association with the TAP complex but is targeted to vesicles, where it binds its ligand. The second unusual feature is that, unlike MHC class I, CD1 molecules have a hydrophobic channel that is specialized for binding hydrocarbon alkyl chains. This confers on CD1 molecules an ability to bind and present a variety of glycolipids.
CD1 molecules are classified into group 1, comprising CD1a, CD1b, and CD1c, and group 2, containing only CD1d; CD1e is considered intermediate. Group 1 molecules bind various microbial glycolipids, phospholipids, and lipopeptide antigens, such as the mycobacterial membrane components mycolic acid, glucose monomycolate, phosphoinositol mannosides, and lipoarabinomannan (Fig. 6.27). Group 2 CD1 molecules are thought to bind mainly self