A structural perspective of how T cell receptors recognize the CD1 family of lipid antigen-presenting molecules

Abstract

The CD1 family of antigen-presenting molecules adopt a major histocompatibility complex class I (MHC-I) fold. Whereas MHC molecules present peptides, the CD1 family has evolved to bind self- and foreign-lipids. The CD1 family of antigen-presenting molecules comprises four members-CD1a, CD1b, CD1c, and CD1d-that differ in their architecture around the lipid-binding cleft, thereby enabling diverse lipids to be accommodated. These CD1-lipid complexes are recognized by T cell receptors (TCRs) expressed on T cells, either through dual recognition of CD1 and lipid or in a new model whereby the TCR directly contacts CD1, thereby triggering an immune response. Chemical syntheses of lipid antigens, and analogs thereof, have been crucial in understanding the underlying specificity of T cell-mediated lipid immunity. This review will focus on our current understanding of how TCRs interact with CD1-lipid complexes, highlighting how it can be fundamentally different from TCR-MHC-peptide corecognition.

Keywords: CD1; T cell recognition; antigen presentation; lipid; lipid analog; structure.

Figure 1

CD1 at a glance.Top, structures of four CD1 isoforms in comparison with an MHC-I molecule (HLA-B∗57:03). Despite sharing similarity of overall β2M-associated fold, MHC-I has a shallow cleft for peptide binding, whereas CD1 molecules possess hydrophobic pockets to accommodate lipids. Middle, top view to the lipid binding pockets of CD1 molecules in comparison with the peptide binding cleft of MHC-I. The pockets A′ and F′ in CD1 molecules, corresponding to A and F in MHC-I, are indicated. Down, surface representation demonstrates the full exposure of the peptide in MHC-I, whereas only the lipid headgroups can protrude out of the binding pockets in CD1 molecules. αGalCer, α-galactosyl ceramide; MHC-I, major histocompatibility complex class I; MPM3, difluoromethylene-mannoside phosphomycoketide; PG, phosphatidylglycerol; PS, phosphatidylserine.

Figure 2

Classes of lipids and hydrophobic compounds presented by CD1. Chemical schematic of different classes of ligands that can bind to CD1.

Figure 3

Overall docking topologies of TCR-CD1-lipid. Two paradigms of TCR–lipid–CD1 interactions. A, type I NKT TCR (NKT15) to CD1d-αGalCer (3VWJ (68)). B, type II NKT TCR (XV19) to CD1d-sulfatide (4EI5 (69)). C, 9C2 γδTCR to CD1-αGalCer (4LHU (28)). D, GEM42 αβTCR to CD1b-GMM (5L2K (53)). E, BK6 αβTCR to CD1a-oleic acid (4X6D (64)). F, CO3 γδTCR to CD1a-sulfatide (7RYN (66)). G, 3C8 αβTCR to CD1c-MAG (6C09 (11)). H, general structure of a T cell receptor (TCR). αGalCer, α-galactosylceramide; MAG, monoacylglycerol; GMM, glucose monomycolate; NKT, natural killer T.

Figure 4

Strategies for the design of synthetic αGalCer analogs. Feasible modifications of αGalCer are indicated in red. αGalCer can be modified in its headgroup as well as the lipid tails, such as altered chain length, unsaturation, or extra conjugation. αGalCer, α-galactosylceramide.