MHCII
Antigen presentation
Antigen presentation
The molecules derived from the MHCII locus require the work of many accessory proteins in order to present peptides to T cells and generate the appropriate immune response. More specifically, this pathway relies on the invariant chain (Ii) and the non-classical MHCII molecule HLA-DM (DM), two chaperones leading to the expression of stable peptide-MHCII complexes (pMHCII) at the plasma membrane. Upon synthesis in the ER, Ii associates with MHCII and targets the resulting complex to the endosomal/lysosomal compartments, commonly termed MIIC. There, Ii is sequentially degraded until only the class II-associated invariant chain peptide (CLIP) portion remains in the MHCII binding groove . Following Ii degradation, DM facilitates the exchange of CLIP for antigenic peptides onto MHCII. The resulting pMHCII then egress to the cell surface where they can ultimately meet cognate TcRs.
The first steps of antigen presentation begin by the the association of MHCII molecules with the invariant chain (Ii) in the endoplasmic reticulum (ER). Homotrimers of Ii bind MHCII chains sequentially, starting with the alpha chain and facilitate the pairing of a beta chain of the same haplotype.
In the MIICs, the increased acidity and the presence of proteases allow for Ii degradation, which occurs in a highly coordinated fashion. This process aims to free MHCIIs from Iiʼs scaffold and to leave only a small portion of Ii, the class II-associated Ii peptide (CLIP), within the peptide-binding groove. The proteolysis steps can be listed as follow: Ii luminal trimerization domain is cleaved first, followed by the trimming of the CLIP extremities, releasing MHCII heterodimers from Iiʼs grasp and mediated targeting. A subsequent intra-membrane cleavage generates the cytoplasmic p10 fragment, reported to induce NFκB.
Put into cellular context, MHCII assembly in the ER, egress into the endosomal compartments and subsequent degradation in the MIICs. Protein endocytosis and degradation is also pictured. In the MIIC, peptides are exchange spontaneously or with the help of DM, which is inhibited while paired with DO. Once stable peptide-MHCII complexes are formed, they gain access to the cell surface where they can be scanned by T cells.
Closer look at the peptide exchange
In DO+ cells, DM-DO complexes egress from the ER to the MIICs (1), in which the increased acidity provokes their dissociation (2). There, spontaneous peptide release and loading occurs due to continuous peptide motion and provides a pool of MHCIIs with partially-bound peptide, susceptible to DM binding (3). DM-binding site is pictured as a slot on the cartoon’s MHCII a-chain. Next, DM facilitates the release of the remainder of the peptide (4) while the resulting DM-empty MHCII complexes can bind new peptides with very rapid kinetics. Weak MHCII binders will go through many cycles of peptide editing by DM, until strong binders induce its dissociation. These stable pMHCIIs may be displayed on the cell surface for many days depending on the APC. In parallel, DM also rescues empty-MHCII before they collapse (5).
