Induction of regulatory functions in BATF3+ B cells through ligand-receptor interactions [CUT&Tag 2]

As “effector” cells, B lymphocytes make antibodies. They also regulate immune functions through ligand-receptor interactions. The limited understanding of regulatory roles of B cells prompted us to develop a workflow that profiles B cell ligand and receptor expression, maps in silico interactions involving ligands with high “specificity scores”, validates the function of top ligand-receptor interactions, and unveils transcription regulation of specific ligands. Using this unbiased approach, here we report the regulatory functions of a new subset of murine B cells that express BATF3 as a hallmark transcription factor. BATF3+ B cells, as generated upon B cell activation by innate TLR and adaptive CD40 and IL-21 receptor signals, lose their effector cell function (making class-switched antibodies) while expressing new ligands, most notably cytokine IL-27 and chemokine CXCL10. As elicited by viral infection and immunization, IL-27+CXCL10+ B cells target effector B cells through the IL-27 receptor and, together with IFNg, optimize the antibody response and anti-viral immunity. Also appearing in tumors and retained there through the autocrine CXCL10-CXCR3 interaction, they enhance B cell expression of immune checkpoint PD-L1 and suppress anti-tumor immunity. Thus, we have identified new regulatory B cells and provided a paradigmatic framework to investigate immune cell communications. Overall design: Wildtype B cells were stimulated with LPS, anti-CD40 plus IL-27 (A21), or LPS plus anti-CD40 and IL-21 (LA21). Batf3 knockout (KO) B cells were stimulated with LPS plus anti-CD40 and IL-21 (LA21). BATF3 ployclonal antibody were used to select regions of interest.