Activated CARD11 accelerates germinal center kinetics, promoting mTORC1 and terminal differentiation

J Exp Med. 2018 Sep 3;215(9):2445-2461. doi: 10.1084/jem.20180230. Epub 2018 Aug 20.


Activating mutations in the adapter protein CARD11 associated with diffuse large B cell lymphomas (DLBCLs) are predicted to arise during germinal center (GC) responses, leading to inappropriate activation of NF-κB signaling. Here, we modeled the B cell-intrinsic impact of the L251P activating mutation in CARD11 (aCARD11) on the GC response. Global B cell aCARD11 expression led to a modest increase in splenic B cells and a severe reduction in B1 B cell numbers, respectively. Following T cell-dependent immunization, aCARD11 cells exhibited increased rates of GC formation, resolution, and differentiation. Restriction of aCARD11 to GC B cells similarly altered the GC response and B cell differentiation. In this model, aCARD11 promoted dark zone skewing along with increased cycling, AID levels, and class switch recombination. Furthermore, aCard11 GC B cells displayed increased biomass and mTORC1 signaling, suggesting a novel strategy for targeting aCARD11-driven DLBCL. While aCARD11 potently impacts GC responses, the rapid GC contraction suggests it requires collaboration with events that limit terminal differentiation to promote lymphoma.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • B-Lymphocytes / immunology*
  • B-Lymphocytes / pathology
  • CARD Signaling Adaptor Proteins / genetics
  • CARD Signaling Adaptor Proteins / immunology*
  • Cell Differentiation / genetics
  • Cell Differentiation / immunology*
  • Germinal Center / immunology*
  • Germinal Center / pathology
  • Lymphoma, Large B-Cell, Diffuse / genetics
  • Lymphoma, Large B-Cell, Diffuse / immunology*
  • Lymphoma, Large B-Cell, Diffuse / pathology
  • Mechanistic Target of Rapamycin Complex 1 / genetics
  • Mechanistic Target of Rapamycin Complex 1 / immunology*
  • Mice
  • Mice, Transgenic
  • Models, Immunological*
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / immunology*
  • Signal Transduction / genetics
  • Signal Transduction / immunology*


  • CARD Signaling Adaptor Proteins
  • Card11 protein, mouse
  • Neoplasm Proteins
  • Mechanistic Target of Rapamycin Complex 1