NKT TCR Recognition of CD1d-α-C-Galactosylceramide

Abstract

NKT cells respond to a variety of CD1d-restricted glycolipid antigens that are structurally related to the prototypic antigen, α-galactosylceramide (α-GalCer). A modified analogue of α-GalCer with a carbon-based glycosidic linkage (α-C-GalCer) has generated great interest because of its apparent ability to promote prolonged, Th1-biased immune responses. Here we report the activation of spleen NKT cells to α-C-GalCer, and related C-glycoside ligands, is weaker than that of α-GalCer. Furthermore, the Vβ8.2 and Vβ7 NKT TCR affinity for CD1d-α-C-GalCer, and some related analogues, is approximately 10-fold lower than that for the NKT TCR-CD1d-α-GalCer interaction. Nevertheless, the crystal structure of the Vβ8.2 NKT TCR-CD1d-α-C-GalCer complex is similar to that of the corresponding NKT TCR-CD1d-α-GalCer complex, although subtle differences at the interface provide a basis for understanding the lower affinity of the NKT TCR-CD1d-α-C-GalCer interaction. Our findings support the concept that for CD1d-restricted NKT cells, altered glycolipid ligands can promote markedly different responses while adopting similar TCR docking topologies.

Structure-Activity Relationship Studies of Novel Glycosphingolipids That Stimulate Natural Killer T-Cells

“…The substantial stability of 10 itself and its ability to activate NK cells might make for large scale IFNproduction. 70) Although X-ray analysis of mouse CD1d/ 10/TCR has been reported, 69,116) the key factor arousing the Th1-type response has not been clarified yet. The progress of further investigation is expected with anticipation.…”

“…Based on X-ray information on mouse and human CD1d/1/TCR complexes, [22][23][24] the spatial relationship between the galactose and the ceramide parts appears to be very important in making a rigid complex with CD1d that shows potent bioactivities. 69) Chen et al reported the synthesis of -galactosylated oxime analog 17, which is also an elongated analog having an extra N-atom, without biological information, in 2010. 83) 3.…”

Decline in peripheral blood NKG2D+CD3+CD56+ NKT cells in metastatic colorectal cancer patients

“…Besides NKT-like cells, a small proportion of Type I NKT (iNKT) cells are CD56+ (40,41). The discrimination between these two (iNKT & NKT-like) subsets requires the use of CD1d loaded with α-GalCer (α-galactosylceramide) (42), lacking in our research. Thus, at this level, we could not determine the type of NKT cells in the patients and controls, and so we reported our results as CD3+CD56+ NKT cells.…”

Mecanismos de activación de las células T asesinas naturales invariantes (iNKT)

“…Por otro lado, el compuesto α-C-GalCer (tabla 1), que tiene un remplazo del oxígeno de unión al azúcar por un carbono, produce una respuesta con tendencia al tipo Th1 (28). Un efecto similar se ha observado con el cambio de un oxígeno por un carbono en la galactosa para crear el compuesto llamado carbasugar (RCAI-56) (17).…”