STAT3 Ser727 phosphorylation is required for regulating the balance of plasma cell differentiation and germinal center B cell proliferation via optimizing STAT3-mediated transcription 2790

Abstract Description IL-21R, which signals via STAT3, is critical for normal germinal center (GC) responses. Though IL-21 promotes STAT3 phosphorylation at Tyr705, STAT3 is also phosphorylated at Ser727, a conserved site across STAT proteins and species. Here we explore the as-yet undefined role of STAT3 p-Ser727 in B cells and GC responses. IL-21 induces STAT3 p-Ser727 in naïve B cells and GC B cells (GCBCs), with higher phosphorylation levels in GCBCs. However, the function of STAT3 p-Ser727 in GCBCs remains unclear. To explore the role of STAT3 p-Ser727 in GCBCs, we utilized mice homozygous for Stat3 S727A allele, which prevents Ser727 phosphorylation. These mice had elevated GCBCs and T follicular helper cells (Tfhs) compared to WT after NP-KLH immunization. As shown by mixed bone marrow (BM) chimeras, the increased GCBCs response in mutated mice is B cell-intrinsic, but Tfhs effect is not T cell-intrinsic. GCBCs in S727A mice proliferate more than WT, while there is no effect on apoptosis. In contrast S727A mice have fewer long-lived plasma cells in BM. Mechanistically, the STAT3 S727A mutation increases STAT3 Tyr705 phosphorylation and nuclear translocation, but suppresses STAT3 target gene transcription. These data reveal that STAT3 p-Ser727 generation is required for STAT3’s maximal transcription and plasma cell differentiation of germinal center B cells, offering insights into both the function of Ser727 phosphorylation as well as the role of STAT3 signaling in B cell immune responses. Funding Sources Supported by NIH R01 AI105018 and R01 AI043603. Topic Categories Immune Response Regulation: Molecular Mechanisms (IRM)