B Cell-Intrinsic Stat3 Regulates The Germinal Center Dark Zone

Abstract Germinal centers (GCs) are sites for antibody diversification, somatic hypermutation (SHM) and antigen specific B cell selection. GCs are anatomically divided into two distinct areas known as dark zone (DZ) and light zone (LZ) where SHM and clonal selection occurs, respectively. Although previous studies have suggested a B cell-intrinsic role of STAT3 in GC maintenance and antibody responses, how STAT3 signaling in B cells may maintain GCs for B cell selection is not clear. Using immunization and infection models, we show that STAT3 in B cells regulates the GC DZ, resulting in decreased high affinity antibody production. STAT3 deficient DZ B cells demonstrate a decreased cell proliferation and increased apoptotic activity. Further, STAT3 deletion in B cells led to defects in plasma cell formation and B cell memory response. Using GC B cell specific STAT3 conditional knockout mice and GC B cell culture system, we show that STAT3 deficient GC B cells display low amounts of FOXO1, a critical transcription factor required for GC DZ program. Transcriptomic analysis of GC B cells from STAT3 deficient and sufficient mice reveals STAT3-mediated gene regulation of multiple cellular pathways known to be involved in GC DZ maintenance. In conclusion, STAT3 signaling in B cells controls the GC DZ, which, in turn, helps maintain GCs for high-affinity antibody production. Our findings identify STAT3 as a novel target for enhancing humoral immunity as well as for the treatment of diseases involving abnormal GC activity.