Lipid and small-molecule display by CD1 and MR1

Abstract

The antigen-presenting molecules CD1 and MHC class I-related protein (MR1) display lipids and small molecules to T cells. The antigen display platforms in the four CD1 proteins are laterally asymmetrical, so that the T cell receptor (TCR)-binding surfaces are comprised of roofs and portals, rather than the long grooves seen in the MHC antigen-presenting molecules. TCRs can bind CD1 proteins with left-sided or right-sided footprints, creating unexpected modes of antigen recognition. The use of tetramers of human CD1a, CD1b, CD1c or MR1 proteins now allows detailed analysis of the human T cell repertoire, which has revealed new invariant TCRs that bind CD1b molecules and are different from those that define natural killer T cells and mucosal-associated invariant T cells.

Figure 1 |. Mammalian CD1 genes.

The tree illustrates the origins of modern species after the key event of the bird-mammal split. The discovery of avian CD1 orthologues indicates the existence of ancestral CD1 genes prior to the bird-mammal split, and CD1 genes are universally or widely conserved in mammals. The number of CD1 genes in rabbits, mice, guinea pigs, primates, dogs, cattle, pigs, horses and chickens^, differ. For guinea pigs, we discovered one CD1 gene in the updated genome, in addition to the published genes^, , which we named after the closest human CD1 orthologue, which was CD1a. All three group 1 CD1 proteins are absent in mice, creating a need for additional experimental models to study CD1a, CD1b and CD1c.

Figure 2 |. CD1- and MR1-presented antigens.

In contrast to the short peptide ligands of MHC class I proteins, CD1 proteins typically present amphipathic lipids derived from self or foreign sources. Most CD1-presented antigens contain two distinct components. The hydrophilic head groups are comprised of carbohydrate, peptide or inorganic esters that protrude from CD1 molecules to contact T cell receptors (TCRs). The flexible aliphatic hydrocarbon chains anchor the ligands within the CD1 cleft. However, not all CD1-presented antigens are amphipathic lipids. Skin oils, including squalene, lack a discernable hydrophilic head group. The MHC class I-related protein (MR1)-presented antigen 5-oxopropylideneamino-6-D-ribitylaminouracil and the CD1d-presented antigen phenyl pentamethyldihydrobenzofuran 5-sulfonate are small molecules that are neither peptides nor lipids.

Figure 3 |. Scaffold and spacer lipids bind to CD1b.

a | A co-crystal study of CD1b bound to antigen (shown in yellow and red), a synthetic sulfoglycolipid analogue known as SGL12 with a combined lipid length of 33 carbons. This structure also detects a second electron density (shown in orange) positioned in the lower chamber of the CD1b groove, within the T’ tunnel. b | CD1b-binding natural scaffold lipids - diacylglycerides and deoxydihydroceramides - are unusually hydrophobic self lipids. The term ‘scaffold’ refers to the location of one particular kind of spacer lipid, which is located at the bottom of the CD1b groove and lifts of the sulfoglycolipid antigen towards the surface.

Figure 4 |. T cell receptor (TCRs) that function through co-recognition.

This figure shows examples of αβ TCRs^{, ,} and a γδ TCR that make direct contact with a hybrid surface formed by the antigen-presenting molecule and the antigen as it protrudes from the groove. The natural killer T (NKT) cell TCR interacts with CD1d displaying α-galactosylceramide (αGalCer); the mucosal-associated invariant T (MAIT) cell TCR interacts with MHC class I-related protein (MR1) displaying 5-oxopropylideneamino-6-D-ribitylaminouracil; the ELS4 TCR interacts with the MHC class I molecule HLA-B35 displaying an Epstein-Barr virus (EBV)-derived peptide; and the 9C2 γδTCR interacts with CD1d displaying αGalCer. The TCR footprint is shown in red in the lower panels. In these four examples the TCR contacts both the antigen-presenting molecule and the bound ligand, so these represent the mechanisms of TCR co-recognition.

Figure 5 |. CD1 proteins have laterally asymmetrical antigen display platforms.

a | The grooves of MHC class I (left) and MHC class II (not shown) proteins are broadly open to solvent, creating a situation in which peptide is presented on both sides of the bisecting plane (dotted line). Most interactions of the peptide with the T cell receptor (TCR) occur near the centre of the platform. By contrast, all four human CD1 antigen-presenting molecules use an asymmetrical antigen display platform. In human CD1 proteins, the α1 and α2 helices connect to form A’ roofs, which cover approximately half of the cleft (red). These roof structures prevent direct TCR binding to antigen positioned on the left side of the platform. Antigens such as sulfatide, ganglioside M2 and phosphomycoketide protrude from the open end of the cleft (green) through a rounded opening known as the F’ portal. The hydrophilic head groups of individual antigens vary in size so that they can protrude minimally or extensively. The site of antigen protrusion is on the right side of the platform, but antigens with large head groups can pivot either to the left, creating an epitope near the centre of CD1, or to the right, creating an ectopic epitope at the extreme right. b | The transparent surface of the CD1b groove demonstrates that it is not a groove-like structure that is broadly exposed to solvent. Instead, the shape of CD1 grooves resembles a boot viewed from the side because the A’ roof creates a constricted, portal-like connection with the TCR contact surface.

Figure 6 |. Direct recognition of CD1a molecules carrying permissive ligands.

a | The T cell receptor (TCR) BK6 forms a left-sided footprint (lower panel, red) that contacts CD1a itself rather than the lipid ligand lysophosphatidylcholine (LPC). b | Permissive lipid ligands act through absence of interference using two proposed mechanisms. Some endogenous lipids have small head groups that are predicted not to protrude substantially from the groove, whereas LPC does protrude from the groove, but takes a rightward position on the surface so that it does not contact a left-binding TCR. c | Based on binary TCR structures^, , non-permissive ligands, such as sphingomyelin, sulfatide and the mycobactin-like lipopeptide, bind in the groove and are thought to have an anti-antigenic function by blocking TCR docking to CD1a. Other non-permissive ligands disrupt a triad of amino acids (R76, E154 and R73) within the A’ roof.