An Interleukin 9-Zbtb18 axis promotes germinal center development of memory B cells

Abstract Germinal centers (GCs) generate humoral memory in the form of long-lived plasma cells and memory B cells (MBCs). MBC development in GCs entail profound changes in states of cell cycle, localization and survival. Whether and how these changes are extrinsically instructed and intrinsically programmed in GC B cells are not well understood. Here we demonstrate that Il-9 instructs MBC development from GCs during the primary response. Il-9 induces expression of Zbtb18, a transcription repressor that is repressed in the bulk of GC cells but highly expressed in GC memory precursor cells and MBCs. While Zbtb18 is dispensable for activation of naïve B cells and for GC formation, it is essential for normal development of GC-derived MBCs. Zbtb18 directly binds to and represses a suite of cyclin and CDK genes to promote quiescence, pro-apoptotic genes Bid and Casp3 to promote survival, and GC-retaining gene S1pr2 to promote GC departure. In the absence of Zbtb18, GCMP cells do not efficiently quit cell cycle to achieve quiescence, do not efficiently downregulate S1pr2 to exit, and they become more prone to die. Our results support that an Il-9-Zbtb18 axis instructs development of functional B-cell memory from GCs.