AKT activity orchestrates marginal zone B cell development in mice and humans

The signals controlling marginal zone (MZ) and follicular (FO) B cell development remain incompletely understood. Here, we show that AKT orchestrates MZ B cell formation in mice and humans. Genetic models that increase AKT signaling in B cells or abolish its impact on FoxO transcription factors highlight the AKT-FoxO axis as an on-off switch for MZ B cell formation in mice. In humans, splenic immunoglobulin (Ig) D+CD27+ B cells, proposed as an MZ B cell equivalent, display higher AKT signaling than naive IgD+CD27− and memory IgD−CD27+ B cells and develop in an AKT-dependent manner from their precursors in vitro, underlining the conservation of this developmental pathway. Consistently, CD148 is identified as a receptor indicative of the level of AKT signaling in B cells, expressed at a higher level in MZ B cells than FO B cells in mice as well as humans. [Display omitted] •AKT signaling in B cells drives MZ B cell development•FoxO1 inactivation is necessary for MZ B cell development•AKT is also distinctively increased in human IgD+CD27+ MZ B cells•CD148 is expressed at higher levels in MZ B cells than FO B cells in mice and humans Cox et al. show that AKT activation biases B cell development toward marginal zone (MZ) B cells with innate functions. CD148 is identified as a receptor indicative of AKT signaling level in B cells, expressed at higher levels in MZ than FO B cells in mice and humans.