INVARIANT CHAIN PROMOTES EGRESS OF POORLY EXPRESSED, HAPLOTYPE-MISMATCHED CLASS-II MAJOR HISTOCOMPATIBILITY COMPLEX A-ALPHA-A-BETA DIMERS FROM THE ENDOPLASMIC-RETICULUM CIS-GOLGI COMPARTMENT

Invariant chain (Ii) is a nonpolymorphic, non-major histocompatibility complex (MHC)-encoded glycoprotein that rapidly associates with newly synthesized class II MHC-alpha and beta-chains in the rough endoplasmic reticulum. This oligomerization of Ii, alpha, and beta and their cotransport within the cell led to speculation that Ii was an essential alpha-beta-transport protein. However, direct tests failed to show an absolute requirement for Ii in class II MHC molecule transport. More recently, it has become clear that different class II alpha-beta-chain combinations vary greatly in their efficiency of cell-surface expression, based largely on the allelic origin of the alpha and beta-amino-terminal regions. Because the previous tests of Ii for a role in class II molecule expression utilized efficiently expressed alpha-beta-combinations, we have reexamined this question with several haplotype-mismatched murine A-alpha and A-beta chain combinations of various potentials for cell-surface expression. Using a transient expression assay in Ii-negative COS cells, we find that many inefficiently expressed alpha-beta combinations show marked augmentation of surface expression upon cosynthesis of Ii. This effect is absent or minimal with evolutionarily coselected, haplotype-matched chains that give efficient expression alone. Biochemical studies show that at least one component of the Ii effect is an increased egress of already formed alpha-beta dimers from the rough endoplasmic reticulum/cis-Golgi. We suggest that these results reflect the interaction of Ii with the peptide-binding domain of the poorly expressed class II molecules, either aiding in maintenance of a transportable conformation or competing with endoplasmic reticulum retention proteins, and thus enhancing movement to the cell surface. These results suggest a complex and variable role for trans-associated-alpha and beta-chains in the immune responses of MHC heterozygotes and provide a method for examining Ii interaction with class II MHC molecules independent of measurement of peptide presentation to T cells.