Invariant chain association with MHC class I: preference for HLA class I/beta 2-microglobulin heterodimers, specificity, and influence of the MHC peptide-binding groove.

MHC class I molecules require the assembly of heavy chain with beta2-microglobulin (beta 2m) and peptide in order to present Ag on the cell surface. Endoplasmic reticulum resident proteins associate with class I molecules and aid assembly. Free class I heavy chains associate with calnexin, which may facilitate association with beta 2m. Invariant chain (Ii) also associates with MHC class I molecules, but its role in class I assembly is not clear. We report here that Ii strongly associates with HLA class I/beta 2m heterodimers, but weakly with free class I heavy chains in HLA-B7-transfected T2 cells. Ii/HLA class I complexes persist stably within the endoplasmic reticulum/cis-Golgi compartment in peptide-processing deficient cells, but are much less prominent in normally processing cells. Furthermore, Ii differentially associates with variant HLA-B7 molecules that have peptide-binding groove mutations, and the degree of association correlates with HLA-B7 variant cell surface expression. Ii also shows HLA class I molecule specificity, associating to a greater degree with HLA-B7 than HLA-A2. Together these observations suggest that Ii stabilizes particular HLA class I/beta 2m heterodimers until peptide is loaded, and that this association may enhance class I cell surface expression.