Role for cathepsin F in invariant chain processing and major histocompatibility complex class II peptide loading by macrophages

The major histocompatibility complex (MHC) class II-associated invariant ch ain (Ii) regulates intracellular trafficking and peptide loading of MHC cla ss II molecules. Such loading occurs after endosomal degradation of the inv ariant chain to a similar to 3-kD peptide termed CLIP (class II-associated invariant chain peptide). Cathepsins L and S have both been implicated in d egradation of Ii to CLIP in thymus and peripheral lymphoid organs, respecti vely. However, macrophages from mice deficient ill both cathepsins S and L can process Ii and load peptides onto MHC class II dimers normally. Both pr ocesses are blocked by a cysteine protease inhibitor, indicating the involv ement of an additional Ii-processing enzyme(s). Comparison of cysteine prot eases expressed by macrophages with those found in splenocytes and dendriti c cells revealed two enzymes expressed exclusively in macrophages, cathepsi ns Z and F. Recombinant cathepsin Z did not generate CLIP from Il-MHC class II complexes, whereas cathepsin F was as efficient as cathepsin S ill CLIP generation. Inhibition of cathepsin F activity and MHC class II peptide lo ading by macrophages exhibited similar specificity and activity profiles. T hese experiments show that cathepsin F, in a subset of antigen Presenting c ells (APCs), can efficiently degrade Ii. Different APCs can thus use distin ct proteases to mediate MHC class II maturation and peptide loading.