Introduction

CD1d is a non-polymorphic antigen-presenting molecule that is structurally related to the MHC class I molecule. CDId molecules are heterodimers that are composed of a heavy chain that is non-covalently associated with ß2-microglobulin (ß2m). The heavy chain is composed of three extracellular domains designated al, a2 and a3 as well as a transmembrane and an intracytoplasmic domain. The antigen-binding cavity is formed from the a I and a2 domains of the heavy chain. These domains comprise two a-helices which flank the opening of the cleft and a ß-sheet floor (see Fig. 1a and b). The cleft is hydrophobic in nature and composed of an A' and an F' pocket (sometimes called C' pocket). Despite the structural similarities between MHC class I and CDId molecules, the unique properties of their antigen-binding cavities enable them to present distinct antigens to the immune system for immune surveillance. MHC class I molecules bind and present peptides, whereas CD1d molecules bind and present a diverse range of hydrophobic lipids from self and foreign sources (Fischer et al., 2004; Giabbai et al., 2005; Kinjo et al., 2005; Mattner et al., 2005; Sriram et al., 2005; Wu et al., 2005; Wu et al., 2006; Wu et al., 2003; Zhou et al., 2004). The localisation of CD1d in late endosomes or lysosomes is ideal for the uptake of foreign lipid antigens, which accumulate in these endocytic compartments during a microbial infection (Kang & Cresswell, 2004). CDId is a key player in our ability to overcome microbial infections because it is able to present foreign lipid antigens to the subset of T cells termed Natural Killer T (NKT) cells.

NKT cells express an aß T cell receptor (TcR) and markers usually associated with NK cells such as NKI.I, members of the Ly-49 and DX5 receptor family, CDI22 and CDI6.

Although previously viewed as a single population of cells, NKT cells are heterogeneous and can be divided into functionally distinct subsets (Crowe et al.,

Fig. 1. Overview of the three-dimensional structure of hCDld. Cartoon representation of hCDld from a) a side-view b) an aerial view of the antigen-binding domain.

2005; Hammond et al., 1999). This review will focus on two NKT cell receptor subsets that are stimulated by the potent agonist a-galactosylceramide (a-GalCer) in the context of CDld (Benlagha et al., 2000; Kawano et al., 1997; Lantz & Bendelac, 1994). These include the invariant NKT (iNKT) cell receptor and Va24 independent TcRs. The iNKT cell receptor is the most studied subset of NKT cell receptors to date and is semi-invariant in nature. The Va24/Ja18 (TRAV10/TRAJ18) and the Vpil-gene segment (TRBV25-1) is preferentially selected in human iNKT cell receptors, whereas in mice the invariant a-chain Va14/Ja18-gene segment is associated with one of three p-chain combinations (VP2, Vp7, VP8.2). The p-chain of iNKT cell receptors typically exhibit a wide diversity of CDR3 junctions such that the CDR3P loop differs in its composition and length and generally exhibits a high degree of natural variability (Matsuda et al., 2001). CDld/a-GalCer specific T cell clones that do not use the Va24 gene segment (Brigl et al., 2006; Gadola et al., 2002; Gadola et al., 2006) will be referred to as Va24 independent TcRs. Interestingly, the Va segment of some of these TcRs has been determined to recombine with the Ja18 segment that is selected in iNKT cell receptors (Brigl et al., 2006; Gadola et al., 2006) (see Table 1). Furthermore, although the Va24 independent TcRs use a selection of Vp segments, they have a bias for the Vp11 chain that is most commonly selected in human iNKT cell receptors (Brigl et al., 2006; Gadola et al., 2002; Gadola et al., 2006) (see Table 2). iNKT cell receptors and Va24 independent TcRs have been shown to 'respond similarly' to a-GalCer (Brigl et al., 2006) and have a similar affinity for CD1d/a-GalCer as do other ap TcRs for peptide/MHC class I (Clements et al., 2006; Ely et al., 2005). Affinities between 4-9 |M (Gadola et al., 2006; Kjer-Nielsen et al., 2006) have recently been reported for human NKT cell receptors,

Table 1. Amino acid residues composing the CDR3a loop in select iNKT and Va24 independent (Va24-) T cell receptors.

TcR

iNKT

CDR3a

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