The role of granzyme B in antigen-presenting cells [thesis]

Timo Trzaska, Universität Ulm
Expression of the serine protease Granzyme B (GrB) in cytotoxic T lymphocytes and natural killer cells has been known for many years. In these cells GrB acts in concert with perforin and kills target cells by cleavage of caspase-3 at aspartic residues, among other cytotoxic pathways. In recent years many new and previously unexpected non-cytotoxic functions and targets of GrB have been identified, e.g. the cleavage of extracellular matrix proteins, cell surface receptors and autoantigens. GrB
more » ... autoantigens. GrB was found in regulatory T and B cells as well as in plasmacytoid dendritic cells and we assume that, despite its well established cytotoxic function, it is a common effector molecule of regulatory immune cells in general. GrB can induce immunogenic cell death by induction of eat-me signals on the cell surface of target cells and can enhance antigen uptake by dendritic cells, subsequent cross-presentation to T cells and their proliferation. In this thesis we show that intravenous immunoglobulin preparations (which are successfully administered in various autoimmune diseases and the therapeutic effect of which may in part depend on GrB) have a mixed effect on the induction of GrB in B cells depending on product and concentration. The phenotype of GrB+ B cells was further characterized with a large array of surface molecules. It was found that GrB+ B cells significantly upregulated CD55, CD147 and MHC I and II molecules, while CD32 was reduced. An effect of Granzyme B on the uptake of antigen from lysed tumor cells by B cells was not observed, which however, may be due to the anti-gen specificity of the B cell receptor. In plasmacytoid dendritic cells (pDCs), which received maturation stimuli (resulting in reduced GrB expression) or when a GrB inhibitor was added, antigen uptake was markedly reduced compared to activated, GrBhigh pDCs. In a co-culture of differentially activated and matured, antigen-pulsed pDCs and allogenic T cells we detected reduced T cell proliferation in conditions where GrB was inhibited or pDCs matured t [...]
doi:10.18725/oparu-37702 fatcat:zkmlt3hir5aupjomeez43xmopm