In Sections 3-24 to 3-27, we introduced NK cells and briefly discussed their activation by members of the MIC gene family. These are MHC class Ib genes that are under a different regulatory control than the classical MHC class I genes and are induced in response to cellular stress (such as heat shock). There are seven MIC genes, but only two—MICA and MICB—are expressed and produce protein products (see Fig. 6.26). They are expressed in fibroblasts and epithelial cells, particularly in intestinal epithelial cells, and have a role in innate immunity or in the induction of immune responses in circumstances in which interferons are not produced. The MICA and MICB proteins are recognized by the NKG2D receptor expressed by NK cells. But in addition, NKG2D is also expressed by γ:δ T cells and some CD8 T cells, and it can activate these cells to kill MIC-expressing targets. NKG2D is an ‘activating’ member of the NKG2 family of NK-cell receptors (see Fig. 3.42); its cytoplasmic domain lacks the inhibitory sequence motif found in other members of this family, which act as inhibitory receptors (see Section 3-26). NKG2D is coupled to the adaptor protein DAP10, which transmits the signal into the interior of the cell by interacting with and activating intracellular phosphatidylinositol 3-kinase.
Even more distantly related to MHC class I genes is a small family of proteins known in humans as the UL16-binding proteins (ULBPs) or the RAET1 proteins (see Fig. 6.26); the homologous proteins in mice are known as Rae1 (retinoic acid early inducible 1) and H60. These proteins also bind NKG2D (see Section 3-27). They seem to be expressed under conditions of cellular stress, such as when cells are infected with pathogens (UL16 is a human cytomegalovirus protein) or have undergone transformation to tumor cells. By expressing ULBPs, stressed or infected cells can bind and activate NKG2D molecules expressed on NK cells, γ:δ T cells, and CD8 cytotoxic α:β T cells, and so be recognized and eliminated.
The human MHC class Ib molecule HLA-E and its mouse counterpart Qa-1 (see Fig. 6.26) have an unusual and somewhat puzzling role in cell recognition by NK cells and CD8 T cells. HLA-E and Qa-1 bind a very restricted subset of nonpolymorphic peptides, called Qa-1 determinant modifiers (Qdm), that are derived from the leader peptides of other HLA class I molecules. These peptide:HLA-E complexes can bind to the inhibitory receptor NKG2A:CD94 expressed on NK cells, and so should inhibit the cytotoxic activity of NK cells. This function might seem redundant, since expression of other MHC class I molecules by cells should prevent NK-cell activation (see Section 3-25). Nonetheless, it has been shown that Qa-1 expression by activated CD4 T cells protects them from lysis by NK cells and so Qa-1 expression by other host cells may provide them with additional protection from being killed by NK cells. HLA-E and Qa-1 can also bind leader peptides from the heat shock protein Hsp60sp, and CD8 T cells that are specific for these complexes have been identified in mice and humans. Some recent evidence suggests that CD8 T cells restricted by HLA-E/Qa-1 may help maintain self-tolerance by killing or suppressing potentially autoreactive T cells.