Exposing the Specific Roles of the Invariant Chain Isoforms in Shaping the MHC Class II Peptidome

Abstract

The peptide repertoire (peptidome) associated with MHC class II molecules (MHCIIs) is influenced by the polymorphic nature of the peptide binding groove but also by cell-intrinsic factors. The invariant chain (Ii) chaperones MHCIIs, affecting their folding and trafficking. Recent discoveries relating to Ii functions have provided insights as to how it edits the MHCII peptidome. In humans, the Ii gene encodes four different isoforms for which structure-function analyses have highlighted common properties but also some non-redundant roles. Another layer of complexity arises from the fact that Ii heterotrimerizes, a characteristic that has the potential to affect the maturation of associated MHCIIs in many different ways, depending on the isoform combinations. Here, we emphasize the peptide editing properties of Ii and discuss the impact of the various isoforms on the MHCII peptidome.

Keywords: MHCII; MHCII trafficking; antigen presentation; di-arginine motif; di-leucine motif; invariant chain; p35.

Figure 1

Portrait of the role of the human invariant chain in MHCII presentation. (A) MHCII α and β chains assemble with Ii in the ER [1]. The four Ii isoforms randomly associate into trimers, some of which bear ER retention motif(s) and/or thyroglobulin domain(s). Unphosphorylated Iip35/p43-containing trimers, associated with MHCIIs or not, exit the ER but are recognized by β-COP and undergo retrograde transport [2]. The MHCII-bound Ii that gets phosphorylated by PKC binds 14-3-3β, thereby preventing β-COP binding and allowing anterograde transport [3]. (B) From the Golgi, the different complexes gain access to the plasma membrane or early endosomes [3]. The complexes at the plasma membrane reach the MHCII-rich compartment (MIIC) after being internalized into clathrin-coated pits [4]. In endosomes, presence of p41/43 will reduce processing by inhibiting cathepsin S (iCAT) and slowing-down Ii processing and/or transport to the cell surface [5]. (C) In multivesicular MIICs, the carboxy-terminal trimerization domain of Ii is cleaved by non-cysteine proteases, generating the p22 fragment. Then, cysteine proteases remove the glycosylated portion to form the p10 fragment before active cathepsin S (aCAT) cuts the anchored portion, leaving CLIP in the MHCII groove. CLIP is then exchanged for an antigenic peptide spontaneously or by DM [6]. Ii degradation frees myosin II, which can restore the cell motility and remodeling of endosomes [7]. (D) Antigens are internalized by pinocytosis or receptor-mediated endocytosis and degraded by proteases, including cathepsins [8]. In the presence of p41/43, processing is more focused given the inactivation of cathepsins. Thus, the MHCIIs that gain access to the plasma membrane present peptides derived from receptor-mediated Ag internalization to CD4⁺ T cells [9].