T lymphocytes have developed the capacity to recognize as antigens a large variety of molecules including peptides, lipids, and vitamin metabolites (Moody DB et al. 2005; Rossjohn J et al. 2015; de Jong A 2015). Specific recognition of lipids by T-cell receptors (TCR) occurs when these molecules form antigenic complexes using functionally nonpolymorphic CD1 molecules (Beckman EM et al. 1994; De Libero G1 & Mori L 2005; Tatituri RV et al. 2013; Van Rhijn I et al. 2015).
Humans express five functional CD1 isotypes (CD1a-e), with CD1e being the only member that does not directly present antigens to T cells (Calabi F et al. 1989; Balk SP et al. 1989; de la Salle H et al. 2005). CD1a, CD1b, CD1c and CD1d are surface expressed proteins that can be found on the plasma membranes of antigen-presenting cells (APC) (Dougan SK et al. 2007). CD1 ectodomains consist of a heavy chain, which folds into three extracellular domains (alpha1, alpha2 and alpha3) noncovalently associated with beta2-microglobulin (B2M) (Moody DB et al. 2005). Antigen-binding grooves nestle between the alpha1 and alpha2 helices and are mostly lined by hydrophobic residues (Zeng Z et al. 1997). This allows the antigenic lipids to be anchored via their hydrophobic chains, so that polar motifs protrude toward the aqueous milieu (Gadola SD et al. 2002; Zajonc DM et al. 2003, 2005; Batuwangala T et al. 2004; Koch M et al. 2005; Zajonc DM et al. 2005; Scharf L et al. 2010; Garcia-Alles LF et al. 2011). Consequently, polar heads establish stimulatory contacts with TCRs, while variation in the number, length and saturation of alkyl chains may contribute to the binding to varying degrees (Borg NA et al. 2007; Garcia-Alles LF et al. 2011; Li Y et al. 2010; Pierce BG et al. 2014). Each of the four CD1 isoforms that directly present antigens to T cells differ in size of the antigen-binding grooves (Zajonc DM et al. 2005; Gadola SD et al. 2002; Zajonc DM et al. 2003, 2005; Batuwangala T et al. 2004; Koch M et al. 2005; Cheng TY et al. 2006; Borg NA et al. 2007; Scharf L et al. 2010; Garcia-Alles LF et al. 2011), intracellular trafficking patterns (Sugita M et al. 1999; Moody DB & Porcelli SA 2003), lipid ligand repertoire (Im JS et al. 2004; Huang S et al. 2011; Ly D & Moody DB 2014), and tissue distribution of expression (Dougan SK et al. 2007). Together with the observation that multiple CD1 isoforms have been maintained throughout mammalian evolution, this argues that each CD1 isoform plays a non-redundant role in the immune system (Dascher CC 2007; de Jong A 2015).
A large spectrum of self- and foreign lipids associates with members of CD1 family (Mattner J et al. 2005; Kinjo Y et al. 2005; Chang DH et al. 2008; Cohen NR et al. 2009; De Libero G et al. 2009; Zajonc DM & Girardi E 2015; Birkinshaw RW et al. 2015; de Jong A 2015). CD1-bound self-derived lipid antigens, including gangliosides, sulfatide, phosphoglycerolipids and sphingomyelin, can stimulate specialized subsets of T cells though the importance of self-lipid interactions with TCRs can vary (Birkinshaw RW et al. 2015; Borg NA et al. 2007; Luoma AM et al. 2013, 2014; Lepore M et al. 2014; Roy S et al. 2016). The ability of of both alphabeta and gammadelta T cells to recognize self lipid loaded CD1 molecules enables these lymphocytes to sense changes in the lipid composition of cells and tissues as a result of infections, inflammation, or malignancies (Brennan PJ et al. 2011; Chang DH et al. 2008; Cohen NR et al. 2009; Luoma et al. 2014; Lepore M et al. 2014; de Jong A 2014, 2015).
The Reactome event shows self lipid-based molecules that have been reported to function as antigens for CD1-restricted T cells (Shamshiev A et al. 2002; Birkinshaw RW et al. 2015; de Jong A 2015).