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To identify new regulators of B cell activation and plasmablast differentiation in the context of the splenic microenvironment, we established an in vivo system for pooled sgRNA CRISPR\/Cas9 screens in immunized mice. To improve the infection efficiency of na\u00efve B cells, we generated Cd23-Cre Rosa26LSL-EcoR\/+ mice exhibiting increased expression of the ecotropic lentivirus receptor EcoR on na\u00efve B cells. Upon adoptive B cell transfer and immunization of recipient mice, 379 sgRNAs, targeting genes with high expression in plasma cells, were analyzed for their effects on plasmablast generation. Gene hits, encoding 23 positive and 18 negative regulators of B cell activation, plasmablast differentiation, or homeostasis, were uniquely identified in these in vivo screens. Validated genes encoded proteins involved in cell adhesion, signal transduction, protein folding, iron transport, and enzymatic processes. 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