The ligands of NKG2D and CD94/NKG2 belong to families of MHC-like molecules that share the important property of being inducible on solid tissue cells upon stress, transformation, and inflammation (reviewed in Lanier 2004; Raulet 2003). This is highly consistent with a role of these NKRs in focusing the activation of effector CTLs on the appropriate tissue target, namely, a cell that not only is expressing antigen but also exhibits signs of distress.
Thus human NKG2D ligands comprise MICA, MICB (Groh et al. 1996) and ULBP1, -2, -3, and -4 (Cosman et al. 2001; Jan Chalupny et al. 2003), which are distantly related to MHC class I, do not bind peptides, and do not require p2-microglobulin for expression. MIC molecules are highly expressed in embryonic tissue but are poorly expressed in adult tissue, with the exception of the colon, which is constitutively colonized by bacteria. MIC molecules can be induced on transformation, infection, or stress in adult tissue (Groh et al. 1996). MICA and MICB are MHC encoded (Bahram et al. 1994) and do not have a homolog in mouse, whereas ULBP genes are non-MHC encoded and are the orthologs of the mouse RAE-1 genes (Radosavljevic et al. 2002). The other mouse NKG2D ligands comprise H60 and MULT-1, which demonstrate relative low homology to RAE-1 (reviewed in Raulet 2003).
The ligand of CD94/NKG2A and CD94/NKG2C receptors is the nonclassic MHC class I molecule HLA-E (Braud et al. 1998; Llano et al. 1998) and its Qa-1 homolog in mouse (Vance et al. 1999) combined with conserved leader peptides of MHC class I molecules. In human, CD94/NKG2A and CD94/NKG2C also recognize HLA-E with the HLA-G leader peptide (Llano et al. 1998; Vales-Gomez et al. 1999). Because CD94/NKG2C is poorly expressed by CTLs, ligand induction should generally translate into an inhibitory signal when target cells express normal levels of MHC class I. In disease conditions such as CMV (Guma et al. 2004) and severe celiac disease (manuscript in preparation) CTLs can express CD94/NKG2C, but they do not express CD94/NKG2A, thus avoiding a conflict between these opposite forms of signaling. Intriguingly, human NKG2E and its splice variant H differ significantly from the other mouse and human NKG2 molecules in the putative ligand binding site, suggesting that they may display specificities in addition to their ability to bind HLA-E with the classic MHC class I leader peptides (Kaiser et al. 2005). The hsp60 leader peptide, which binds HLA-E but is not recognized by CD94/NKG2A or CD94/NKG2C (Michaelsson et al. 2002), or other viral and stress induced peptides might be interesting candidates because they would allow targeting of CTL responses against damaged or infected tissue cells. Interestingly, as reported for MIC (Wu et al. 2002), HLA-E recognition can also be TCR me diated (Garcia et al. 2002; Pietra et al. 2001), in particular, HLA-E-restricted CTLs with TCR specificity for hsp60 leader peptide (Davies et al. 2003) and CMV peptides (Romagnani et al. 2004) have been identified in mouse and human, respectively.
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