Studies of protease function in antigen-presenting cells

Erwin Schrödinger Fellowship J 1977 Studies of protease function in antigen-presenting cells Edda FIEBIGER 09.10.2000 Major histocompatibility complex (MHC) class II molecules bind and display antigenic peptides as class II-pepjide complexes on the surface of antigen-presenting cells (APCs) for the recognition of T helper cells. Proteolysis controls at least two key events in class II-dependent antigen presentation: the generation of antigenic peptides and the processing of the invariant chain (li), a major class 11 chaperon. Resent studies show the major contribution of endo/lysomal cathepsins, (Cat). CatS is the most potent catalyst of li degradation in vitro and in vivo. However, class II-peptide complexes are detected on the cell surface of CatS -/- APCs and can elicit T cell responses. In a first set of experiments, I used the iodinated active site label JPM to characterice the protease expression of various human and murine APCs. In addition to the definition of protease expression patterns, these experiments depicted a new, yet not defined, enzyme. Furthermore, studies with CatS/H-2M double knockout mice demonstrated that MHC class 11-peptide complexes in APCs from CatS knockout mice are generated in a H-2M-dependent fashion. This result explains the partly unperturbed T cell response detected under Cat S-deficient conditions. Further experiments will focus on the characterisation of antigen presentation properties of the CatS/H-2M double deficient APCs and the indentification of the new cathepsin. The identity of proteases involved in the degradation of antigens taken up via endocytosis is poorly understood. Thus, degradation studies with allergens as model antigens will be performed. In summary, these experiments shall help the understanding of the role of proteolysis in antigen presentation and lead to the development of new strategies for immuneintervention.