Intracellular BH3 profiling reveals shifts in anti-apoptotic dependency in B-cell maturation and activation

Abstract

Apoptosis is critical to B-cell maturation, but studies of apoptotic regulation in primary human B cells is lacking. Previously, we found that infecting human B cells with Epstein-Barr virus induces two different survival strategies (Price et al., 2017). Here, we sought to better understand the mechanisms of apoptotic regulation in normal and activated B cells. Using intracellular BH3 profiling (iBH3), we defined the Bcl2-dependency of B-cell subsets from human peripheral blood and tonsillar lymphoid tissue as well as mitogen-activated B cells. We found that naive and memory B cells were BCL-2 dependent, while germinal center B cells were MCL-1 dependent and plasma cells were BCL-XL dependent. Proliferating B cells activated by CpG or CD40L/IL-4 became more dependent upon MCL-1 and BCL-XL. As B-cell lymphomas often rely on survival mechanisms derived from normal and activated B cells, these findings offer new insight into potential therapeutic strategies for lymphomas.