Characterizing the impact of the microenvironment on plasma cell function

点击翻译按钮获取中文摘要

As important effector cells of humoral immunological memory, plasma cells can survive for long periods in the body. In doing so, they retain their ability to secrete antibodies in large quantities, which usually have a protective effect, but in some cases - for example, in various autoimmune diseases - can also cause damage to the body. The survival of plasma cells depends crucially on their microenvironment. Long-lived plasma cells reside preferentially in the bone marrow, where they are found in close contact with stromal cells. Those stromal cells form a niche that promotes plasma cell survival, together with cytokines that originate from hematopoietic cells. However, the exact cellular and molecular composition of the tissue niches for plasma cells has not yet been deciphered. In addition, it is not clear how long-lived plasma cells cope with the challenge of adapting to changing environmental conditions, such as variations in the supply of nutrients. In this project, we first aim to comprehensively characterize the tissue niches for plasma cells using state-of-the-art imaging methods. We will combine methods of multiplex histology with spatially resolved transcriptome analyses. Furthermore, we want to elucidate the mechanisms that allow plasma cells to functionally adapt to different conditions in their niches. Here, we focus on the supply of nutrients, which we first investigate in vitro. We will test the hypothesis that cytoplasmic calcium acts as a transmitter of metabolic stress in plasma cells and investigate whether the cells can dynamically adapt their antibody production to the changing availability of nutrients. In addition, it will be analyzed whether plasma cells switch their metabolism and perform increased autophagy in times of nutrient deficiency. Using our proprietary methods of longitudinal functional intravital microscopy in bone marrow, we plan to test our hypotheses in vivo. Finally, the effects of interventions affecting plasma cell metabolism on the function of these cells and on bone marrow composition and niches will be investigated. The insights gained in this project will provide a mechanistic explanation of how plasma cells manage to perform their metabolically demanding functions over long periods of time. Therefore, this study can help to develop strategies that promote the survival of protective plasma cells. On the other hand, it may reveal new ways to therapeutically influence pathogenic plasma cells, via interfering with their metabolism.