The processing and presentation of lipids and glycolipids to the immune system

Abstract

The recognition of CD1-lipid complexes by T cells was discovered 20 years ago and has since been an emerging and expanding field of investigation. Unlike protein antigens, which are presented on MHC class I and II molecules, lipids can only be presented by CD1 molecules, a unique family of MHC-like proteins whose singularity is a hydrophobic antigen-binding groove. The processing and loading of lipid antigens inside this groove of CD1 molecules require localization to endosomal and lysosomal subcellular compartments and their acidic pHs. This particular environment provides the necessary glycolytic enzymes and lipases that process lipid and glycolipid antigens, as well as a set of lipid transfer proteins that load the final version of the antigen inside the groove of CD1. The overall sequence of events needed for efficient presentation of lipid antigens is now understood and presented in this review. However, a large number of important details have been elusive. This elusiveness is linked to the inherent technical difficulties of studying lipids and the lipid-protein interface in vitro and in vivo. Here, we will expose some of those limitations and describe new approaches to address them during the characterization of lipids and glycolipids antigen presentation.

Keywords: CD1; T-cell receptors; antigen presentation/processing; lipid mediators; natural killer T cells.

Figure 1. Comparison of the binding grooves of human and mouse CD1 isoforms

A: Protein sequence comparison of the binding groove of human CD1a, b, c, d, and mouse CD1d1. All residues composing the surface of the binding groove are boxed with a dashed outline. In mCD1d1, residues composing the A’ pocket are boxed in dark green, residues composing the F’ pocket are boxed in light green, and residues composing the entrance portal are boxed in pink. Of note is the prevalence of hydrophobic residues that contribute to the binding groove surface. B: Side view of the binding groove of mCD1d1 with the α1 chain in the foreground and the α2 chain in the background. Residues and their respective surfaces composing the A’ pocket are shaded dark green, residues and their respective surfaces composing the F’ pocket are shaded in light green, and residues and their respective surfaces composing the entrance portal are shaded pink (visualization was done with the Chimera software from UCSF(98) using pdb#1CD1. C: Top view of the binding groove of mCD1d1 with the α1 on the bottom and α2 chain on top. Residues and surfaces are shaded as in Figure 1B.

Figure 2. Cell biology of CD1d molecules

First, the CD1d mRNA is translated into the endoplasmic reticulum (E.R.), where it undergoes chaperone-assisted folding via interaction with calnexin (CNX), calreticulin (CALR), and ERp57 until it forms a heterodimer with β2-microglobulin and associate or not with the invariant chain (Ii). Also in the E.R., microsomal triglyceride transfer protein (MTP) may play a role in loading some lipids to CD1d. After association with β2-microglobulin, CD1d is transported through the Golgi to the cell surface. It is internalized through interaction between its cytoplasmic tail and the AP-3 adaptor. This interaction and its disruption will allow trafficking through the endocytic pathway, and delivery to the late endosome and lysosome. Association with the invariant chain in the E.R. results in CD1d entering the trans-Golgi network, where it is directly transported to the late endosome and lysosome. In the late endosome and lysosome, lipid processing proteins alter lipids for pH-dependent loading to CD1d via NPC2, and saposins A, B, C, and D. The lipid-loaded CD1d then traffics to the cell surface, where it presents its lipid antigen to T cells.