Ligand-receptor interactions induce and mediate regulatory functions of BATF3⁺ B cells

B cells express many protein ligands, yet their regulatory functions are incompletely understood. We profiled ligand expression across murine B sublineage cells, including those activated by defined receptor signals, and assessed their regulatory capacities and specificities through in silico analysis of ligand-receptor interactions. Consequently, we identified a B cell subset that expressed cytokine interleukin-27 (IL-27) and chemokine CXCL10. Through the IL-27–IL-27 receptor interaction, these IL-27/CXCL10-producing B cells targeted CD40-activated B cells in vitro and, upon induction by immunization and viral infection, optimized antibody responses and antiviral immunity in vivo. Also present in breast cancer tumors and retained there through CXCL10-CXCR3 interaction–mediated self-targeting, these cells promoted B cell PD-L1 expression and immune evasion. Mechanistically, Il27 and Cxcl10 transcription was induced by synergizing Toll-like receptor (TLR) and CD40 signals and driven by coinduced transcription factor BATF3, which directly targeted these genes. By applying a discovery framework focusing on regulatory cells, our findings expand the recognized scope of B cell regulatory functions.