Fig. 6.27 CD1c binds microbial lipids for presentation to iNKT cells. Top panel: the structure of mannosyl-β1-phosphomycoketides (MPMs) from the cell walls of Mycobacterium tuberculosis (Mtb) (R = C7H15) and M. avium (R = C5H11). Middle panel: MPM (stick figure) bound to CD1c (purple) as viewed from the top, facing the surface of the cell bearing CD1c. Bottom panel: side view of MPM bound to CD1c. The general resemblance with peptide:MHC complexes is apparent. Note: the long acyl chain of MPM extends deep into the binding groove of CD1c, to beneath the α1 helical domain. Courtesy of E. Adams.
lipid antigens such as sphingolipids and diacylglycerols. Structural studies show that the CD1 molecule has a deep binding groove into which the glycolipid antigens bind (Fig. 6.28). Unlike the binding of peptide to MHC, in which the peptide takes on a linear, extended conformation, CD1 molecules bind their antigens by anchoring the alkyl chains in the hydrophobic groove, which orients the variable carbohydrate headgroups (or other hydrophilic parts of these molecules) so that they protrude from the end of the binding groove, allowing recognition by the T-cell receptors on CD1-restricted T cells.
The T cells that recognize lipids presented by CD1 molecules are largely negative for CD4 and CD8 expression, although some express CD4. Most of the T cells recognizing lipids presented by group 1 CD1 molecules have a diverse repertoire of α:β receptors, and respond to these lipids presented by CD1a, CD1b, and CD1c. In contrast, CD1d-restricted T cells are less diverse, many using the same TCRα chain (Vα24–Jα18 in humans), but they also express NK-cell receptors. These CD1-restricted T cells are called invariant NKT (iNKT) cells.
One recognized ligand for CD1d molecules is α-galactoceramide (α-GalCer), which was isolated from an extract of marine sponge. Related glycosphingolipids are produced by various bacteria, including Bacteroides fragilis, which is present in the normal human microbiota. When α-galactoceramide is bound to CD1d, it forms a structure that is recognized by many iNKT cells. The ability of iNKT cells to recognize different glycolipid constituents from microorganisms presented by CD1d molecules places them in an ‘innate’ category, while their possession of a fully rearranged T-cell receptor, despite its relatively limited repertoire, makes them ‘adaptive.’
CD1 proteins have evolved as a separate lineage of antigen-presenting molecules able to present microbial lipids and glycolipids to T cells. Just as peptides are loaded onto classical MHC proteins at various cellular locations, the various CD1 proteins are transported differently through the endoplasmic reticulum and endocytic compartments; this provides access to different lipid antigens. Transport is regulated by an amino acid sequence motif at the terminus of the cytoplasmic domain of the CD1 protein through interaction with adaptor-protein (AP) complexes. CD1a lacks this binding motif and moves to the cell surface, where it is transported only through the early endocytic compartment. CD1c and CD1d have motifs that interact with the adaptor AP-2 and are transported through early and late endosomes; CD1d is also targeted to lysosomes. CD1b and mouse CD1d bind AP-2 and AP-3 and can be transported through late endosomes, lysosomes, and the MIIC. CD1 proteins can thus bind lipids delivered into and processed within the endocytic pathway, such as by the internalization of mycobacteria or the ingestion of mycobacterial lipoarabinomannans mediated by mannose receptors.