Mathematical modeling reveals a complex network of signaling and apoptosis pathways in the survival of memory plasma cells

The long-term survival of memory plasma cells is conditional on the signals provided by dedicated survival niches in the bone marrow organized by mesenchymal stromal cells. Recently, we could show that plasma cell survival requires secreted factors such as APRIL and direct contact to stromal cells, which act in concert to activate NF-kB- and PI3K-dependent signaling pathways to prevent cell death. However, the precise dynamics of the underlying regulatory network are confounded by the complexity of potential interaction and cross-regulation pathways. Here, based on flow-cytometric quantification of key signaling proteins in the presence or absence of the required survival signals, we generated a quantitative model of plasma cell survival. Our model emphasizes the non-redundant and essential nature of the two plasma cell survival signals APRIL and stromal cell contact, providing resilience to endoplasmic reticulum stress and mitochondrial stress, respectively. Importantly, the modeling approach allowed us to unify distinct data sets and derive a consistent picture of the intertwined signaling and apoptosis pathways regulating plasma cell survival.