Invariant chain controls H2-M proteolysis in mouse splenocytes and dendritic cells

The association of invariant (Ii) chain with major histocompatibility compl ex (MHC) class II dimers is required for proper antigen presentation to T c ells by antigen-presenting cells. Mice lacking Ii chain have severe abnorma lities in class II transport, T cell selection, and B cell maturation. We d emonstrate here that H2-M, which is required for efficient class II antigen ic peptide loading, is unexpectedly downregulated in splenocytes and mature dendritic cells (DCs) from Ii(-/-) mice. Downregulation reflects an increa sed rate of degradation in Ii(-/-) cells. Degradation apparently occurs wit hin lysosomes, as it is prevented by cysteine protease inhibitors such as E 64, but not by the proteasome inhibitor lactacystin. Thus, Ii chain may act as a lysosomal protease inhibitor in B cells and DCs, with its deletion co ntributing indirectly to the loss of H2-M.