Immunoproteasome Research

Immunoproteasome Research (Meiners lab)

One focus of research is the immunoproteasome, a specialized form of the proteasome that plays an important role in regulating immune responses. In immune cells, the immunoproteasome (i20S) is constitutively expressed, while in non-immune cells the standard proteasome (s20S) predominates, buti20Scan be induced by inflammatory signals and infections (Figure 1). The immunoproteasome has a different proteolytic activity than the s20S and plays a key role in the regulation of immune and stress responses, such as the activation of CD8 T cells by MHC class I antigen presentation in viral and tumor diseases (Figure 2). However, the exact function of the immunoproteasome in immune cells, in the response to infections, and in chronic lung diseases such as COPD, pulmonary fibrosis, and lung tumors is not well understood.

Leibniz-Gemeinschaft „ImmunoPROteasomes in LUNG health and disease“ – PRO-LUNG

We here explore the concept that the inducible nature of the immunoproteasome enables dynamic adaptation of proteasome function in immune and stress responses. In particular, we aim to understand whether standard, immuno- and the various types of mixed proteasomes have distinct functions e.g. by localizing to distinct cell types or subcellular sites, degrading different substrates, or by interacting with defined proteasome regulators. Solving these questions is key for a detailed understanding of the function of the immunoproteasome in health and disease. It will pave the way for validation of the immunoproteasome as a therapeutic target allowing specific inhibition of single or multiple immunoproteasome subunits in disease with novel site-specific immunoproteasome inhibitors that are currently being developed.

Leibniz Center for Infection: “Sex-specific regulation of immunoproteasome function determines response to infection“ (together with Bianca Schneider, FZB)

In this project, we investigate the (biological) sex-specific regulation of the immunoproteasome and whether this might contribute to the stronger immune responses against infections in females. We are using influenza and tuberculosis-related infection models in female and male mice to dissect the immunoproteasome related immune response as well as in vitro cellular models for sex-hormone treatment. The aim is to unravel the molecular basis of sex-related regulation of the immunoproteasome, which may enable us to develop sex-specific diagnostic tools and target the immunoproteasome therapeutically in a sex-related manner.

CRC 1713 Maternal Immune Activation

Priority Program SPP2453 Mitostress

Regulation of MrgprB2-mediated mast cell activation by tetraspanin CD37

Mast cells (MCs) are long-lived sentinel cells of the immune system that control allergic and inflammatory responses. While the tetraspanin CD37 is known to be an important regulator of signal transduction in B cells, its function in mast cell activation remains poorly understood. Here, we investigate how CD37 regulates mast cell activation by comparing two genetic models of CD37 deficiency. Mast cells from conventionally CD37-deficient mice were hypersensitive to IgE-independent, MrgprB2-mediated stimulation. In contrast, mast cells from mast cell-specific CD37 knockout mice showed no altered activability and responded normally to IgE-dependent and independent stimuli. The observed IgE-independent hypersensitivity in conventionally CD37-deficient mice could be due to an off-target effect. To test this hypothesis, we are reconstituting CD37 expression in CD37-deficient mast cells using lentiviral transduction. In addition, we have identified a neighboring gene that is a potential new regulator of mast cell activation.

Modulation of B-cell function through epitope-specific CD37 targeting in mice

CD37 is a glycosylated membrane protein that is strongly expressed in B cells. Like other tetraspanins, CD37 is involved in the regulation of incoming signals, lateral membrane protein interactions, and intracellular signal processing. In this project, we characterize CD37-specific monoclonal antibodies and investigate the effects of epitope-specific CD37 targeting in vitro and in vivo. The CD37-specific monoclonal antibodies recognize two different CD37 epitopes.  The binding of the antibodies to CD37 leads to the induction of B cell death in vitro. In mice, the application of CD37 AK also leads to a reduction in various B cell populations. Nevertheless, we also observed a specific immune response to injected antibodies, which indicates the activation of certain B cell populations. In further experiments, we will investigate the mechanisms responsible for B cell depletion that could be used for the treatment of chronic lung diseases. The enhanced induction of an immune response, on the other hand, is important for the development of new vaccine technologies.