Integration of cell signaling and metabolism in B cells    

It is becoming increasingly apparent that lymphocyte metabolism and signaling are highly connected and functionally interdependent. While growth factor signaling can alter nutrient uptake and utilization, oxygen and nutrient availability can skew cell fate decisions and functions. In recent years, considerable effort has been put into elucidating the regulation of cell metabolism in T cells. However, comparably little is known about B cells. Our data suggest that germinal center B cells are larger, contain more mitochondria, and consume more glucose than resting B cells. In addition, unlike naïve B cells, we found germinal center B cells to reside in a hypoxic environment and to express Hif1α, a transcription factor known to accumulate under hypoxia. Thus, to maintain viability, germinal center B cells need to be able to balance cell growth and division with nutrient and oxygen availability. In our previous work, we have found glycogen synthase kinase 3 (GSK3) to play an essential role in the maintenance of metabolic homeostasis in B cells (Fig. 1). GSK3-deficient B cells showed an increase in cell size, mitochondrial content, and oxygen consumption, resulting in increased proliferation. However, they also displayed decreased viability under metabolically challenging conditions. In vivo, this dysregulated growth control resulted in impaired survival of GSK3-deficient germinal center B cells. Our goal is to further analyze the metabolic profile of different B cell subsets, to assess how these cells respond to metabolic stress and to elucidate the role of the PI3K signaling pathway in regulating these processes. To better understand how PI3K/GSK3-dependent signaling regulates B cell metabolism we will utilize different mouse models displaying enhanced PI3K signaling or increased β-Catenin accumulation in B cells. β-Catenin accumulates in GSK3-deficient B cells and our preliminary data suggest that β-Catenin accumulation accelerates B cell proliferation to a subset of stimuli. We aim to determine how β-Catenin accumulation affects B cell signaling and metabolism and seek to analyze B cell development and differentiation in mice expressing hyper-stabilized β-Catenin.

Fig. 1. B cell growth and proliferation need to be coordinated with nutrient availability and the cells’ capacity to process these nutrients. Unrestricted cell growth can lead to a rapid depletion of nutrients and a metabolic collapse. GSK3-mediated signaling plays an important role in maintaining B cell homeostasis by restricting metabolic activity and cell growth.