IL-4 Licenses B Cell Activation Through Cholesterol Synthesis

IL-4 is a pleiotropic cytokine that was first identified as a B cell co-mitogen over 30 years ago1. However, how IL-4 signaling mechanistically supports B cell proliferation is incompletely understood. Here, we find that the cholesterol biosynthetic program is transcriptionally upregulated by IL-4 signaling during the early B cell response to influenza virus infection and is required for B cell activation in vivo. Induction of lipid synthesis genes required both STAT6 and SREBP2 transcription factors, allowing IL-4 activated B cells to enter the cell cycle and proliferate in the absence of lipids. Genetic inhibition of de novo cholesterol synthesis via SREBP2 deletion reduced plasmablasts and subsequent germinal center B cell formation at steady state and following influenza infection. SREBP2-deficency blocked IL-4 mediated cell cycle entry, ER expansion, and subsequent proliferation in a cholesterol dependent manner. Further mechanistic studies revealed that ER cholesterol content promoted sustained STAT6 signaling associated with ER expansion and B cell survival. In sum, we demonstrate that the well-known ability of IL-4 to act as a B cell growth factor is through a previously unknown rewiring of specific lipid anabolic programs, relieving sensitivity of cells of environmental nutrient availability.