LKB1 inhibition of NF‐κB in B cells prevents T follicular helper cell differentiation and germinal center formation

Abstract

© 2015 The Authors. T-cell-dependent antigenic stimulation drives the differentiation of B cells into antibody-secreting plasma cells and memory B cells, but how B cells regulate this process is unclear. We show that LKB1 expression in B cells maintains B-cell quiescence and prevents the premature formation of germinal centers (GCs). Lkb1-deficient B cells (BKO) undergo spontaneous B-cell activation and secretion of multiple inflammatory cytokines, which leads to splenomegaly caused by an unexpected expansion of T cells. Within this cytokine response, increased IL-6 production results from heightened activation of NF-κB, which is suppressed by active LKB1. Secreted IL-6 drives T-cell activation and IL-21 production, promoting T follicular helper (T FH ) cell differentiation and expansion to support a ~100-fold increase in steady-state GC B cells. Blockade of IL-6 secretion by BKO B cells inhibits IL-21 expression, a known inducer of T FH -cell differentiation and expansion. Together, these data reveal cell intrinsic and surprising cell extrinsic roles for LKB1 in B cells that control T FH -cell differentiation and GC formation, and place LKB1 as a central regulator of T-cell-dependent humoral immunity. Synopsis LKB1-mediated signaling in B cells is shown to have both cell-intrinsic and cell-extrinsic roles in regulating the differentiation of T FH cells and the formation of germinal centers, which occurs in part through enhanced IL-6 secretion. Mice with B cells lacking LKB1 (BKO) form large GCs without specific antigen exposure BKO B cells are activated and secrete T FH -cell-polarizing cytokines, including IL-6 IL-6 from BKO B cells induces IL-21 in CD4 + T cells to optimize T FH -differentiation BKO B cells have increased nuclear accumulation of NF-κB LKB1-mediated signaling in B cells is shown to have both cell-intrinsic and cell-extrins ic roles in regulating the differentiation of T FH cells and the formation of germinal centers, which occurs in part through enhanced IL-6 secretion.