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

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

Author information

1
Center for Immunity and Immunotherapies, Seattle Children's Research Institute, Seattle, WA.
2
Department of Immunology, University of Washington School of Medicine, Seattle, WA.
3
Department of Pediatrics, University of Washington School of Medicine, Seattle, WA.
4
Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA.
5
Fred Hutchinson Cancer Research Center, Seattle, WA.
6
University Children's Hospital Basel, University of Basel, Basel, Switzerland.
7
Department of Pharmacology, University of Washington School of Medicine, Seattle, WA.
8
Center for Immunity and Immunotherapies, Seattle Children's Research Institute, Seattle, WA drawling@u.washington.edu.

Abstract

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.

PMID:
30127060
PMCID:
PMC6122963
DOI:
10.1084/jem.20180230
[Indexed for MEDLINE]
Free PMC Article

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