Non-apoptotic FAS signaling controls mTOR activation and extrafollicular maturation in human B cells
Julian Staniek, Tomas Kalina, Geoffroy Andrieux, Melanie Boerries, Iga Janowska, Manuel Fuentes, Paula Díez, Marina Bakardjieva, Jitka Stančíková, Jan Raabe, Julika Neumann, Sabine Schwenk, Leonardo Arpesella, Jan Stuchlý, Vladimı́r Beneš, Rodrigo García-Valiente, Jonatan Fernández-García, Rita Carsetti, Eva Piano Mortari, Albert Català, Oscar De La Calle-Martin, Georgios Sogkas, Bénédicte Neven, Frédéric Rieux‐Laucat, Aude Magérus, Olaf Neth, Peter Olbrich, Reinhard Voll, Laia Alsina, Luís M. Allende, Luis Ignacio González‐Granado, Chiara Böhler, Jens Thiel, Nils Venhoff, Raquel Lorenzetti, Klaus Warnatz, Susanne Unger, Maximilian Seidl, Dirk Mielenz, Pascal Schneider, Stephan Ehl, Anne Rensing‐Ehl, Cristian R. Smulski, Marta Rizzi
Abstract
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.