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

Abstract

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 (TFH ) 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 TFH -cell differentiation and expansion. Together, these data reveal cell intrinsic and surprising cell extrinsic roles for LKB1 in B cells that control TFH -cell differentiation and GC formation, and place LKB1 as a central regulator of T-cell-dependent humoral immunity.

• Authors: Nicole C Walsh, Lynnea R Waters, Jessica A Fowler, Mark Lin, Cameron R Cunningham, David G Brooks, Jerold E Rehg, Herbert C Morse 3rd, Michael A Teitell
• Journal: EMBO reports (EMBO Rep) Vol. 16 Issue 6 Pg. 753-68 (Jun 2015) ISSN: 1469-3178 [Electronic] England
• PMID: 25916856 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2015 The Authors.

Chemical References

• Interleukin-6
• Interleukins
• NF-kappa B
• Protein Serine-Threonine Kinases
• Stk11 protein, mouse
• AMP-Activated Protein Kinases
• interleukin-21

Topics

• AMP-Activated Protein Kinases
• Animals
• B-Lymphocytes (immunology, metabolism)
• Cell Differentiation
• Germinal Center (physiology)
• Interleukin-6 (immunology, metabolism)
• Interleukins (immunology)
• Lymphocyte Activation
• Mice
• NF-kappa B (genetics, metabolism)
• Protein Serine-Threonine Kinases (genetics)
• T-Lymphocytes, Helper-Inducer (immunology, physiology)