An interleukin-9-ZBTB18 axis promotes germinal center development of memory B cells

Abstract

Memory B cell (MBC) development from germinal centers (GCs) entails profound changes in cell cycling, localization, and survival. Here, we examined the mechanisms that induce the memory program, focusing on interleukin (IL)-9, given its importance for normal recall antibody responses. Using adoptive transfer and radiation chimera models, we found that T cell-derived IL-9 was required for MBC development and function. By contrast, B cells deficient in IL-9 generated functionally normal MBCs that support antibody recall normally. IL-9 induced expression of the transcriptional repressor ZBTB18 in GC memory precursor cells and MBCs. ZBTB18 was dispensable for naive B cell activation and GC formation but required for the development of GC-derived MBCs. ZBTB18 directly repressed the expression of a suite of genes encoding cyclin and cyclin-dependent kinases, pro-apoptotic genes Bid and Casp3, and the GC-retaining factor S1pr2. Lack of IL-9-mediated instruction or intrinsic programming by ZBTB18 impaired GC-derived MBC development and antibody recall. Thus, an IL-9-ZBTB18 axis instructs the development of functional B cell memory from GCs.

Keywords: ZBTB18; germinal center; interleukin-9; memory B cells.