Individual cathepsins degrade immune complexes internalized by antigen-presenting cells via Fc gamma receptors

We have analyzed the intracellular degradation of an immune complex after i ts Fc gammaR-mediated uptake in antigen-presenting cells (APC). Mice that l ack the cathepsins (Cat) S, L, B and D allowed us to assess the direct cont ribution of these individual proteases to the processing events observed. C atS and CatB mediate the bulk of degradation of the Ig-I-125- labeled F(ab' )(2) immune complex delivered via Fc gammaR, while CatL and CatD are dispen sable. CatS and CatB are involved in independent processing pathways and ca n substitute in part for each other's absence. The combined ablation of bot h proteases reduces the rate of degradation observed by > 80 %. CatB is req uired for the generation of F(ab')23, a predominant degradation intermediat e smaller by similar to3 kDa than the I-125-labeled F(ab')a itself. In addi tion, absence of CatB in vivo significantly affects the activity pattern of the remaining cysteine proteases. Thus, we conclude that CatB is a key enz yme for the proper degradation of an immune complex taken up by Fc gammaR a nd for the control of protease activity in the endocytic pathway of APC.