THE MHC CLASS II-ASSOCIATED INVARIANT CHAIN - A MOLECULE WITH MULTIPLE ROLES IN MHC CLASS-II BIOSYNTHESIS AND ANTIGEN PRESENTATION TO CD4(-CELLS() T)

The MHC class II-associated invariant chain (Li) plays a central role in the biological function of MHC class II molecules. Ii is a type II membrane glycoprotein that is synthesized as different isoforms that i nclude a major 31 kDa isoform (p31/p33) and a minor 41 kDa isoform (p4 1) in both, mice and humans. All isoforms share several common regions acting at different steps in the process that lead to functional clas s II molecule/peptide complexes. In the ER, two C-terminal extracytopl asmic regions of Ii are required for class II assembly: the 153-183 re gion is involved in the formation of Ii trimers and the 80-104 region mediates binding with class II molecules giving rise to nonamers. Ii a ssociation with class II molecules prevents both aggregation of class II dimers and binding with endogenous ER-derived peptides. In addition , two motifs in the cytosolic N-terminal region of Ii direct class II nonamers toward specialized endosomal compartments where peptide loadi ng occurs. In these compartments, Ii undergoes proteolytic degradation leaving only CLIP (residues 80-104) associated with Class II. CLIP mo dulates loading of class II molecules in endosomes and is removed from the MHC class LT groove by monomorphic MHC class II molecules, H2-M o r HLA DM, in mouse and human, respectively. The roles of Ii in antigen presentation to MHC class II-restricted T cells and in CD4(+) T cell development are discussed in this review.