The crystal structure of human CD1d with and without α-galactosylceramide

Abstract

The glycolipid alpha-galactosylceramide binds with high affinity to CD1d and stimulates natural killer T cells. Here we report the crystal structure of human CD1d in complex with synthetic alpha-galactosylceramide at a resolution of 3.0 A. The structure shows a tightly fit lipid in the CD1d binding groove, with the sphingosine chain bound in the C' pocket and the longer acyl chain anchored in the A' pocket. We also present the CD1d structure without lipid, which has a more open conformation of the binding groove, suggesting a dual conformation of CD1d in which the 'open' conformation is more able to load lipids. These structures provide clues as to how CD1 molecules load glycolipids as well as data to guide the design of new therapeutic agents.

CD1d-restricted iNKT cells, the ‘Swiss-Army knife’ of the immune system

“…Interestingly, the length of the lipid chain occupying this F' channel was shown to modulate the affinity of the iNKT TCR [79λ]. Because conformational changes between empty and antigen-loaded CD1d molecules have been observed in this region of CD1d [80], it is possibility that the iNKT TCR might essentially recognize a change in CD1d conformation following antigen loading.…”

Structural Characterization of Mycobacterial Phosphatidylinositol Mannoside Binding to Mouse CD1d

“…Various foreign ligands can activate iNKT cells, such as the nonmammalian glycolipid, ␣-galactosylceramide (␣-GalCer) (12), microbial ␣-glycuronosylceramides (13,14) (containing either glucuronic acid or galacturonic acid (GalA-GSL)), mycobacterial PIM4 (15), as well as the self-ligand isoglobotrihexosylceramide (iGB3) (16). Crystal structures of CD1d in complex with ␣-GalCer or GalA-GSL (17)(18)(19) have revealed the exquisite hydrogen-bonding network between the ␣-linked carbohydrate headgroup and CD1d, which has not been seen in any other CD1 complex, including human CD1a-sulfatide (20), CD1a-lipopeptide (21), CD1b-PI (22), CD1b-glucosemonomycolate (23), or mouse CD1d-phosphatidylcholine (CD1d-PC) (24).…”

Harnessing the antibacterial and immunological properties of mucosal-associated invariant T cells in the development of novel oral vaccines against enteric infections

“…The most commonly available form of a-Galcer, KRN7000, comprises an a-linked galactose head group and a ceramide base composed of an 28-carbon phytosphingosine chain and a 26-carbon acyl chain. a-Galcer has been shown to bind to both murine and human CD1d [28] and the structure of the a-Galcer/CD1d complex has been described [29].…”

“…More recently Lee et al [46] characterized circulating MAIT cells in a large sample of 133 healthy adults and reported high variability in circulating MAIT cell numbers across subjects (0.19-21.7%). Although no significant differences in numbers between males and females were found there was a significant decrease in MAIT cell numbers in elderly subjects (n = 45, ages 61-92) versus young subjects (n = 44, ages [21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40].…”