MHC class II association with lipid rafts on the antigen presenting cell surface

Abstract

MHC class II (MHC-II) molecules function by binding peptides derived from either self or foreign proteins and expressing these peptides on the surface of antigen presenting cells (APCs) for recognition by CD4 T cells. MHC-II is known to exist on clusters on the surface of APCs, and a variety of biochemical and functional studies have suggested that these clusters represent lipid raft microdomain-associated MHC-II. This review will summarize data exploring the biosynthesis of raft-associated MHC-II and the role that lipid raft association plays in regulating T cell activation by APCs. This article is part of a Special Issue entitled: Nanoscale membrane organisation and signalling.

Keywords: Antigen presenting cell; Lipid raft; MHC class II; T lymphocyte.

Figure 1. Topological Model of MHC-II movement from intralumenal vesicles of MVB to the plasma membrane

MHC-II are present on lipid raft intraluminal vesicles (ILVs) with their peptide-binding grooves exposed to the antigenic peptide-containing lumen of the MVB. A pMHC-II containing ILV (indicated by red membrane) moves toward the MVB limiting membrane (step 1), docks with (step 2) and fuses with the limiting membrane (steps 3 & 4). Continued outward budding from the limiting membrane (step 5) leads to ILV fission from the limiting membrane and release of a membrane-derived transport vesicle (step 6). This transport vesicles docks with the plasma membrane (step 7) and the docked membranes fuse (steps 8 & 9), thereby depositing a “MHC-II raft” generated from ILV membrane into the plasma membrane.

Figure 2. Model of MHC-II-Invariant chain complex-dependent pMHC-II concentration in lipid rafts

Two MHC-II αβ-Ii nonameric complexes are present in an ILV-derived lipid raft microdomain (surrounded by the red border) containing large amounts of “relevant” antigenic peptides (indicated in yellow, left panel). Following Ii degradation, six MHC-II αβ-CLIP complexes are present in this same microdomain (center panel). Following CLIP removal by HLA-DM, six MHC-II αβ-peptide complexes are formed that are enriched in “relevant” antigenic peptides (in yellow) that are all present within a single membrane microdomain (right panel).

Figure 3. Newly-arrived pMHC-II complexes are clustered on the DC surface

Immature DCs were incubated in with HEL protein, washed, and activated with LPS for 12 hr. The DCs were stained live with a mAb that only recognizes the I-A^k-HEL_(46–61) complexes. Aw3.18.14. The cells were analyzed by confocal immunofluorescence microscopy and a single 0.8 μm thick optical section is shown (left panel). The distribution of these newly-arrived pMHC-II complexes on the DC surface was also determined using “plasma membrane rips” and analysis by immunoelectron microscopy (right panel) (Reprinted with permission from reference [16].