Lipid-antigen presentation by CD1 is crystal clear

Abstract

Molecular recognition of foreign or cancerous antigens by T cells requires antigen presentation by the MHC – dual recognition mode of T-cell receptors (TCRs). Peptide antigens are presented by classical MHC, whereas the non-classical MHC, CD1, presents lipid antigens, for example, mycobacterial phospholipids, glycolipids and self-gangliosides. Although peptide–MHC (pMHC) structures have been shown at an atomic resolution for years, lipid–MHC structures have not yet been seen. Gadola et al. [1xStructure of human CD1b with bound ligands at 2.3A, a maze for alkyl chains. Gadola, S.D. et al. Nat. Immunol. 2002; 3: 721–726Crossref | Scopus (177)See all References][1] recently solved the crystal structures of human CD1b (hCD1b) complexed with two lipid ligands, phosphatidylinositol or ganglioside GM2 at 2.3 A and 2.8 A, respectively.Using a modified in vitro refolding technique, the authors obtained hCD1b heavy chain, β2m, lipid complexes and their crystals. The overall structure of lipid–hCD1b represents the pMHC structure and is similar to the only previously known CD1 structure, mouse CD1d (mCD1d), in that the bound lipids were not crystal clear [2xCrystal structure of mouse CD1: an MHC-like fold with a large hydrophobic binding groove. Zeng, Z. et al. Science. 1997; 277: 339–345Crossref | PubMed | Scopus (492)See all References][2]. The striking feature of the lipid–CD1b complex structure is the ligand-binding grooves formed between the α1 and α2 domains. Similar to mCD1d, but different from the classical MHC, the ligand-binding grooves of hCD1b are almost entirely composed of hydrophobic amino acids, which would facilitate the binding of lipid antigens. Unlike mCD1d, in which only two hydrophobic binding pockets have been seen in the antigen-binding groove [2xCrystal structure of mouse CD1: an MHC-like fold with a large hydrophobic binding groove. Zeng, Z. et al. Science. 1997; 277: 339–345Crossref | PubMed | Scopus (492)See all References][2], the lipid-binding groove of hCD1b is composed of a series of interconnected hydrophobic pockets, tunnels and channels. The authors describe this as a maze for lipid-binding.The five CD1 molecules in humans are divided into two groups: group 1 consists of CD1a, CD1b, CD1c and CD1e; CD1d belongs to group 2. Previous functional analysis shows that the common motif for CD1 lipid-ligands is one or more acyl or alkyl chains. The crystal structures of hCD1d have shown that the alkyl chains of the glycolipid occupy the interlinked hydrophobic channels in the antigen-binding groove. This maze-like super-channel structure of the lipid-binding groove is predicted to bind lipid antigens with alkyl chains that can reach 60–70 carbons in length. In this way, the hCD1b could present lipid antigens of any length derived from bacterial pathogens. The authors also found that some detergents used for in vitro refolding occupied some parts of the super-channels, and might act as chaperones for lipid antigen binding to CD1, although this remains to be investigated.This paper, for the first time, provides us with the structural basis of lipid-antigen presentation by non-classical MHC CD1b at atomic level, and this might also be true for other CD1 molecules.