Interplay between carbohydrate and lipid in recognition of glycolipid antigens by natural killer T cells

Abstract

Natural killer T (NKT) cells are a T cell subpopulation that were named originally based on coexpression of receptors found on natural killer (NK) cells, cells of the innate immune system, and by T lymphocytes. The maturation and activation of NKT cells requires presentation of glycolipid antigens by CD1d, a cell surface protein distantly related to the major histocompatibility complex (MHC)-encoded antigen presenting molecules. This specificity distinguishes NKT cells from most CD4(+) and CD8(+) T cells that recognize peptides presented by MHC class I and class II molecules. The rapid secretion of a large amount of both Th1 and Th2 cytokines by activated NKT cells endows them with the ability to play a vital role in the host immune defense against various microbial infections. In this review, we summarize progress on identifying the sources of microbe-derived glycolipid antigens recognized by NKT cells and the biochemical basis for their recognition.

Fig. 1

Structures of synthetic αGalCer and natural microbial lipid Ags. αGalcer has a galactosyl sugar head group and a ceramide (enclosd by a larger solid line box) lipid backbone containing a sphingosine base (enclosed in a dot line internal box), connected by a 1–1' α linkage. The lipid moiety of B. burgdorferi Ag BbGL-II is a diacylglycerol, containing two fatty acid chains, R1 and R2, which are described in Table 1. GlcA-GSL-1, GalA-GSL-1, GSL-4A, and BbGL-II are the names given to purified antigens, which in some cases have heterogeneity.

Fig. 2

Comparison of αGalCer, GalA-GSL, BbGL-IIc, and Glc-DAG-s2 binding to mCD1d before and after TCR engagement. (Top) Glycolipid ligand presentation shown in “TCR view” before TCR binding. Note how the galactose of BbGL-IIc and the glucose of Glc-DAG-s2 lose intimate contacts with α2-helix of mouse CD1d but instead rotate counter-clockwise (~60°) toward Asp80 (D80) of α1-helix, in contrast to αGalCer. (Bottom) Glycolipid bound in the TCR containing ternary complexes shown in the same view as the top, but with the bound TCR removed for clarity. Note that the TCR forces both the galactose of BbGL-IIc as well as the glucose of Glc-DAG-s2 into a position similar to that of αGalCer and GalA GSL before TCR engagement. This structural change induced upon TCR binding is necessary to allow for the conserved TCR binding footprint on CD1d. Also, note how the TCR is able to induce the formation of the F' roof in all CD1d-glycolipid complexes that do not have a preformed F' roof (e.g. αGalCer, top panel).