Efficient cell surface expression of class II MHC molecules in the absence of associated invariant chain

The intracytoplasmic forms of class II (or Ia) major histocompatibility complex heterodimers are associated with a third glycoprotein, termed the invariant chain (Ii). This specific interaction has led to the view that Ii plays a necessary role in the assembly, intracellular transport, and/or membrane insertion of Ia molecules. To test this hypothesis directly, we have transfected complementary DNA clones that encode murine class II alpha and beta chains into cells that do not express any endogenous Ii messenger RNA (mRNA) (COS-7 and BALB/c 3T3 cells). After DNA-mediated gene transfer, significant cell surface expression of Ia was observed in transient expression assays using COS- 7 cells and a stable expression system using BALB/c 3T3 cells. Furthermore, the total levels of class II alpha and beta mRNA were similar in Ii- cells (transfected BALB/c 3T3) and in Ii+ cells (B cell hybridoma) that expressed nearly identical amounts of surface Ia, suggesting that the efficiency of Ia expression was equivalent in the two cell types and, therefore, independent of Ii. These results indicate that the physiologic role for Ii is not simply to mediate membrane expression of Ia molecules, and that alternative hypotheses concerning the true function of this molecule need to be considered.