Characterizing the impact of the microenvironment on plasma cell function

浆细胞作为体液免疫记忆的重要效应细胞，可以在体内长期存活。在这样做的过程中，它们保留了大量分泌抗体的能力，这通常具有保护作用，但在某些情况下，例如在各种自身免疫性疾病中，也会对身体造成损害。浆细胞的存活关键取决于它们的微环境。长寿的浆细胞优先存在于骨髓中，在那里它们与基质细胞密切接触。这些基质细胞与源自造血细胞的细胞因子一起形成促进浆细胞存活的生态位。然而，浆细胞组织壁龛的确切细胞和分子组成尚未被破译。此外，目前尚不清楚长寿的浆细胞如何应对适应不断变化的环境条件的挑战，例如营养物质供应的变化。在这个项目中，我们首先旨在利用最先进的成像方法全面表征浆细胞的组织壁龛。我们将结合多重组织学和空间分解转录组分析的方法。此外，我们希望阐明允许浆细胞在其壁龛中适应不同条件的功能机制。在这里，我们关注营养的供应，我们首先在体外研究。我们将验证细胞质钙在浆细胞中作为代谢应激的传递者的假设，并研究细胞是否可以动态地适应其抗体生产以改变营养物质的可用性。此外，还将分析在营养缺乏时浆细胞是否会改变其代谢并增加自噬。利用我们专有的骨髓纵向功能活体显微镜方法，我们计划在体内验证我们的假设。最后，我们将研究影响浆细胞代谢的干预措施对这些细胞功能以及骨髓成分和生态位的影响。在这个项目中获得的见解将为浆细胞如何在长时间内执行其代谢要求功能提供机制解释。因此，本研究有助于制定促进保护性浆细胞存活的策略。另一方面，它可能揭示通过干扰致病性浆细胞的代谢来治疗性地影响它们的新方法。

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.