Structures and functions of microbial lipid antigens presented by CD1

The CD1 family of proteins has evolved to bind a range of endogenous and foreign lipids and present these at the cell surface for antigen-specific recognition by T cells. The distinct intracellular trafficking pathways of CD 1 molecules indicate that collectively, they have the potential to survey the endocytic system widely for antigen, consistent with a role in the presentation of lipids derived from intracellular microbial pathogens. In keeping with this idea, CDla, CDlb, CDlc and CDld have now been shown to present foreign lipid antigens derived from mycobacteria, Gram-negative bacteria and also protozoan species to T cells. These antigens are extremely diverse chemically, and include naturally occurring lipopeptide, glycolipid and phospholipid structures that are distinct from mammalian lipids. CD1-restricted mycobacterial lipids defined to date derive from the highly complex microbial cell envelope. They play a variety of physiological roles for the microbe, including formation of the plasma membrane and protective cell wall and as metabolic intermediates in iron-scavenging pathways. In each case, alkyl chains of CD 1-restricted lipid antigens are accommodated within a deep hydrophobic groove in the membrane-distal alphal-alpha2 domains of the CD1 molecule, with hydrophilic elements solvent-exposed and accessible for recognition by the T cell receptor. Variation in the number, length and saturation of alkyl chains, and the precise chemistry and chirality of the lipid headgroup, clearly exert dominant influences on antigenicity, mediated by effects on CD1 binding and T cell receptor recognition. In the context of structural studies of CD1-lipid complexes, these data suggest that the CD1 isoforms have evolved binding specificities for different classes of foreign lipids, and strongly support a model for antigen recognition involving fine discrimination of lipid headgroup components by the alpha beta T cell receptor. In this review, we summarise our current knowledge of foreign lipid antigens bound by CD 1, focusing on the roles their distinct structural features play in presentation and T cell antigen recognition, and their likely function in antimicrobial T cell responses.