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Non-apoptotic FAS signaling controls mTOR activation and extrafollicular maturation in human B cells
J. Staniek, T. Kalina, G. Andrieux, M. Boerries, I. Janowska, M. Fuentes, P. Díez, M. Bakardjieva, J. Stancikova, J. Raabe, J. Neumann, S. Schwenk, L. Arpesella, J. Stuchly, V. Benes, R. García Valiente, J. Fernández García, R. Carsetti, E. Piano...
Science immunology.
2024 ;
9 (91) :
eadj5948.
[pub] 20240112
Jazyk angličtina Země Spojené státy americké
Typ dokumentu časopisecké články
Perzistentní odkaz
https://www.medvik.cz/link/bmc24007589
- MeSH
- apoptóza genetika MeSH
- hypergamaglobulinemie * MeSH
- lidé MeSH
- lymfoproliferativní nemoci * genetika MeSH
- TOR serin-threoninkinasy MeSH
- zárodečné centrum lymfatické uzliny MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Defective FAS (CD95/Apo-1/TNFRSF6) signaling causes autoimmune lymphoproliferative syndrome (ALPS). Hypergammaglobulinemia is a common feature in ALPS with FAS mutations (ALPS-FAS), but paradoxically, fewer conventional memory cells differentiate from FAS-expressing germinal center (GC) B cells. Resistance to FAS-induced apoptosis does not explain this phenotype. We tested the hypothesis that defective non-apoptotic FAS signaling may contribute to impaired B cell differentiation in ALPS. We analyzed secondary lymphoid organs of patients with ALPS-FAS and found low numbers of memory B cells, fewer GC B cells, and an expanded extrafollicular (EF) B cell response. Enhanced mTOR activity has been shown to favor EF versus GC fate decision, and we found enhanced PI3K/mTOR and BCR signaling in ALPS-FAS splenic B cells. Modeling initial T-dependent B cell activation with CD40L in vitro, we showed that FAS competent cells with transient FAS ligation showed specifically decreased mTOR axis activation without apoptosis. Mechanistically, transient FAS engagement with involvement of caspase-8 induced nuclear exclusion of PTEN, leading to mTOR inhibition. In addition, FASL-dependent PTEN nuclear exclusion and mTOR modulation were defective in patients with ALPS-FAS. In the early phase of activation, FAS stimulation promoted expression of genes related to GC initiation at the expense of processes related to the EF response. Hence, our data suggest that non-apoptotic FAS signaling acts as molecular switch between EF versus GC fate decisions via regulation of the mTOR axis and transcription. The defect of this modulatory circuit may explain the observed hypergammaglobulinemia and low memory B cell numbers in ALPS.
B Cell Unit Immunology Research Area Bambino Gesù Children's Hospital IRCCS Rome Italy
CIBSS Centre for Integrative Biological Signalling Studies University of Freiburg Freiburg Germany
Department of Hematology Institut de Recerca Hospital Sant Joan de Déu Barcelona Barcelona Spain
Department of Immunology Hospital Universitario 12 de Octubre Madrid Spain
Department of Immunology Leiden University Medical Center Leiden Netherlands
Department of Immunology University Hospital Zurich Zurich Switzerland
Department of Pathology University Medical Center Freiburg Freiburg Germany
Department of Rheumatology and Immunology Hannover Medical School Hannover Germany
Division of Rheumatology and Clinical Immunology Medical University Graz Graz Austria
Faculty of Biology University of Freiburg Freiburg Germany
Genomics Core Facility European Molecular Biology Laboratory Heidelberg Germany
German Cancer Consortium Heidelberg Germany
Immunology Department Hospital de la Santa Creu i Sant Pau Barcelona Spain
Citace poskytuje Crossref.org
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