B cell depletion is a highly effective therapy in multiple sclerosis (MS), reducing inflammation and restoring immune balance. In this issue of the JCI, Wei et al. used single-cell RNA-Seq and flow cytometry, identifying the comprehensive effects of B cell depletion on the immune response, including an increase in antiinflammatory cerebrospinal fluid macrophages and elevated TNF-α expression by peripheral CD16+ monocytes. The authors also detected shifts in T cell populations that resulted in reduced myelin-reactive CD4+ T cells and the expansion of TIGIT+ Tregs. The findings uncover immunoregulatory mechanisms and suggest therapeutic strategies for MS and other autoimmune disorders.