LKB1 inhibition of NF-κB in B cells prevents T follicular helper cell differentiation and germinal center formation.
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.
Department of Pathology & Laboratory Medicine, University of California, Los Angeles, CA, USA.
Nicole C
NC
Walsh
Molecular Biology Institute, University of California, Los Angeles, CA, USA.
Lynnea R
LR
Waters
Department of Pathology & Laboratory Medicine, University of California, Los Angeles, CA, USA.
Jessica A
JA
Fowler
Department of Pathology & Laboratory Medicine, University of California, Los Angeles, CA, USA.
Mark
M
Lin
Department of Microbiology, Immunology and Molecular Genetics and UCLA AIDS Institute University of California, Los Angeles, CA, USA.
Cameron R
CR
Cunningham
Department of Microbiology, Immunology and Molecular Genetics and UCLA AIDS Institute University of California, Los Angeles, CA, USA.
David G
DG
Brooks
Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN, USA.
Jerold E
JE
Rehg
Virology and Cellular Immunology Section, Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases National Institutes of Health, Rockville, MD, USA.
Herbert C
HC
Morse
Department of Pathology & Laboratory Medicine, University of California, Los Angeles, CA, USA Molecular Biology Institute, University of California, Los Angeles, CA, USA Broad Stem Cell Research Center, Departments of Pediatrics and Bioengineering, California NanoSystems Institute, and Jonsson Comprehensive Cancer Center University of California, Los Angeles, CA, USA mteitell@mednet.ucla.edu.
Michael A
MA
Teitell
D055372:AMP-Activated Protein Kinases; D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology* / Q000378:metabolism*; D002454:Cell Differentiation; D018858:Germinal Center / Q000502:physiology*; D015850:Interleukin-6 / Q000276:immunology / Q000378:metabolism; D007378:Interleukins / Q000276:immunology; D008213:Lymphocyte Activation; D051379:Mice; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology* / Q000502:physiology; D000098546:Interleukin-21
D015850:Interleukin-6; D007378:Interleukins; D016328:NF-kappa B; D017346:Protein Serine-Threonine Kinases; C491654:Stk11 protein, mouse; D055372:AMP-Activated Protein Kinases; D000098546:Interleukin-21
     NF‐κB; B cell; TFH
                differentiation; germinal center