Invariant Chain Structure and MHC Class II Function

Abstract

Major histocompatibility complex (MHC) class II molecules go to extraordinary lengths to make sure that they bind to peptides generated in the endosomal–lysosomal system (reviewed byCresswell 1994). First, in the endoplasmic reticulum (ER), newly synthesized class II α and β chains associate with the invariant (Ii) chain to form a complex that itself is incapable of binding peptides. This complex contains three class II αβ dimers associated with an Ii chain trimer. Following transit of the αβIi complex through the Golgi apparatus, targeting signals in the cytoplasmic domain of the Ii chain drive the complex into the endosomal–lysosomal pathway. Once in this pathway, the Ii chain is proteolytically degraded, leaving a small fragment (the class II–associated Ii chain peptide [CLIP]) bound to the released αβ dimers. Interaction of αβCLIP complexes in a specialized lysosome-like compartment with another class II–related αβ dimer, called HLA-DM in the human system and H2-M in mice, drives out the residual CLIP and allows the class II molecules to bind lysosomally generated peptides (reviewed byRoche 1995; Miyazaki et al. 1996 [this issue of Cell; Martin et al. 1996 [this issue of Cell). The peptide-loaded class II molecules, the majority of which are not substrates for HLA-DM, then leave this compartment, designated the MHC class II compartment, by an unknown route to be expressed on the cell surface and surveyed by CD4+ T lymphocytes.