Abstract
The germinal center (GC) reaction is essential for orchestrating humoral immunity by producing plasma cells (PCs) and memory B cells (MBCs). TET2, an α-ketoglutarate-dependent dioxygenase, plays a critical role in B-cell exit from the GC and in plasma cell differentiation. Moreover, TET2 functions as a tumor suppressor in diffuse large B-cell lymphoma (DLBCL), with mutations frequently observed in the ST2 DLBCL subgroup, which is marked by elevated NF-κB and PI3K signaling and predominant expression of IgG B-cell receptors (BCRs). We used a combination of in vivo mouse models and in vitro differentiation systems to investigate the effects of Tet2 deficiency on IgG1+ GC B-cells. We performed flow cytometry, gene expression, and DNA methylation analysis to assess differentiation, proliferation, and molecular alterations. Tet2-deficient IgG1+ GC B-cells displayed impaired differentiation into both PCs and MBCs, accompanied by enhanced proliferation. These cells exhibited hypermethylation and repression of the Nfkbia locus, increased activation of the NF-κB subunit c-Rel, and sustained high levels of surface IgG1. Upon recall immunization, Tet2-deficient IgG1+ MBCs failed to efficiently differentiate into PCs, resulting in their accumulation and further GC expansion. These findings demonstrate that Tet2 is essential for balancing proliferation and terminal differentiation of IgG1+ GC B-cells during the humoral response. The impaired regulation of this balance due to Tet2 loss provides mechanistic insight into a contributory pathway that may facilitate DLBCL transformation in TET2-mutated cases.
