show Abstracthide AbstractB cells differentiate into antibody-producing plasma cells, which are critical for humoral immunity, autoimmunity, and vaccine responses. Despite the importance of environmental stressors on regulating humoral immune responses, the influence of pH on PC differentiation has not been described. Here, we identified SLC4A7, a sodium/bicarbonate cotransporter, as a selective regulator of PC differentiation. SLC4A7 deletion impaired the formation of PCs and humoral immunity to influenza A virus infection in mice. Mechanistically, we find that SLC4A7 prevents acidification of intracellular pH and thus maintains lysosomal function and mTORC1 activity. Loss of SLC4A7 suppresses PC differentiation under conditions of extracellular acidosis in vitro and in a mouse model of metabolic acidosis. Here we reveal a novel relationship between the regulation of intracellular pH by SLC4A7 and mTORC1-dependent PC differentiation and humoral immunity. Overall design: To investigate the pathways dysregulated downstream of SLC4A7 deletion, we sorted in vitro-differentiated CD138+ plasma cells (PCs) and CD138- non-PCs from Slc4a7-KO and WT murine B cells. B cells were stimualted with NIH3T3 feeder cells expressing CD40L and BAFF, in the presence of IL-4.