Csk restrains BCR-mediated ROS production and contributes to germinal center selection and affinity maturation

Compared with naïve B cells, the B cell receptor (BCR) signal in germinal center (GC) B cells is attenuated; however, the significance of this signaling attenuation has not been well defined. Here, to investigate the role of attenuation of BCR signaling, we employed a Csk mutant mouse model in which Csk-deficiency in GC B cells resulted in augmentation of net BCR signaling with no apparent effect on antigen presentation. We found that Csk is required for GC maintenance and efficient antibody affinity maturation. Mechanistically, ROS-induced apoptosis was exacerbated concomitantly with mitochondrial dysfunction in Csk-deficient GC B cells. Hence, our data suggest that attenuation of the BCR signal restrains hyper-ROS production, thereby protecting GC B cells from apoptosis and contributing to efficient affinity maturation. Germinal centers (GCs) are the primary site where B cells undergo affinity maturation, the process whereby the average affinity of antibodies increases with time after immunization. To investigate the role of B cell receptor signaling in GC B cell selection, we analyzed the transcriptome of Csk-deficient GC light zone B cells by RNA-seq. Samples consist of 3 Csk(+/+) and 2 Csk(f/f) biological replicates.