FcγRIIb on B Cells and Myeloid Cells Modulates B Cell Activation and Autoantibody Responses via Different but Synergistic Pathways in Lupus-Prone Yaa Mice

C57BL/6 (B6).FcγRIIb −/− . Yaa mice spontaneously develop lethal lupus nephritis. To define the cell type–specific role of FcγRIIb in Yaa -associated lupus, we established B cell– (CD19 Cre . Yaa ), myeloid cell– (C/EBPα Cre . Yaa ), and dendritic cell– (DC) (CD11c Cre . Yaa ) specific FcγRIIb-deficient B6. Yaa mouse strains. CD19 Cre . Yaa mice developed milder lupus than B6.FcγRIIb −/− . Yaa mice, indicating that FcγRIIb deficiency on B cells is not sufficient for the development of severe disease. Surprisingly, C/EBPα Cre . Yaa mice also showed autoantibody production and mild lupus similar to that in CD19 Cre . Yaa mice, whereas CD11c Cre . Yaa mice stayed disease free. These observations indicate that FcγRIIb deficiency in B cells and myeloid cells, but not DCs, contributes to the severe disease in B6.FcγRIIb −/− . Yaa mice. Flow cytometric analysis showed that the frequency of peripheral Gr-1 − but not Gr-1 + monocyte was increased in B6.FcγRIIb −/− . Yaa and C/EBPα Cre . Yaa but not CD19 Cre . Yaa mice, suggesting a link between FcγRIIb deficiency on myeloid cells and the high frequency of Gr-1 − monocytes. RNA sequencing revealed that compared with Gr-1 + monocytes, Gr-1 − monocytes expressed higher levels of the B cell–stimulating cytokines BSF-3, IL-10, and IL-1β, the DC markers CD11c, CD83, and Adamdec1, and the antiapoptotic factors Bcl2 and Bcl6. In conclusion, in Yaa -associated lupus nephritis, FcγRIIb on B cells and myeloid cells modulates B cell activation via different but synergistic pathways. Gr-1 − monocytes are the most likely candidate myeloid cells involved.