Activated CARD11 accelerates germinal center kinetics, promoting mTORC1 and terminal differentiation.
J Exp Med
; 215(9): 2445-2461, 2018 09 03.
Article
em En
| MEDLINE
| ID: mdl-30127060
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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Linfócitos B
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Transdução de Sinais
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Diferenciação Celular
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Linfoma Difuso de Grandes Células B
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Modelos Imunológicos
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Centro Germinativo
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Proteínas Adaptadoras de Sinalização CARD
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Alvo Mecanístico do Complexo 1 de Rapamicina
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Proteínas de Neoplasias
Idioma:
En
Ano de publicação:
2018
Tipo de documento:
Article