THE PROTEOLYTIC ENVIRONMENT INVOLVED IN MHC CLASS II-RESTRICTED ANTIGEN PRESENTATION CAN BE MODULATED BY THE P41 FORM OF INVARIANT CHAIN

During biosynthesis, MHC class II associates with invariant chain whic h exists in two forms, p31 and p41. Both forms of invariant chain prev ent peptide binding to class II, facilitate transport, and enhance cla ss II localization to Ag-processing compartments, In spite of these sh ared functions, presentation of some Ags can be selectively enhanced b y expression of p41, Here we show that p41 can function as a protease inhibitor: 1) the functional and biochemical consequences of p41 expre ssion can be mimicked by inhibiting cysteine proteases in vivo; 2) the amount of intracellular active cysteine proteases is dramatically dec reased in p41-positive cells; and 3) a polypeptide corresponding to th e p41-unique region is a potent inhibitor of cathepsin L in vitro, The se data suggest that p41 can enhance Ag presentation by reducing the p roteolytic activity of the Ag-processing compartment, thus protecting a subset of antigenic epitopes from excessive degradation.