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

Center for Chronic Immunodeficiency University Medical Center Freiburg Faculty of Medicine University of Freiburg Freiburg Germany

Center for Pediatrics and Adolescent Medicine University Medical Center Freiburg Faculty of Medicine University of Freiburg Freiburg Germany

CIBSS Centre for Integrative Biological Signalling Studies University of Freiburg Freiburg Germany

Clinical Immunology and Primary Immunodeficiencies Unit Department of Pediatric Allergy and Clinical Immunology Hospital Sant Joan de Déu Barcelona Barcelona Spain

Department of Hematology Institut de Recerca Hospital Sant Joan de Déu Barcelona Barcelona Spain

Department of Immunobiology Faculty of Biology and Medicine University of Lausanne Lausanne Switzerland

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 Medicine and General Cytometry Service Nucleus Proteomics Unit CIBERONC CB16 12 00400 Cancer Research Center Universidad de Salamanca Salamanca Spain

Department of Paediatric Haematology and Oncology 2nd Faculty of Medicine Charles University Prague Czech Republic

Department of Paediatric Infectious Diseases Rheumatology and Immunology Hospital Universitario Virgen del Rocio Universidad de Sevilla CSIC Red de Investigación Traslacional en Infectología Pediátrica RITIP Sevilla Spain

Department of Pathology University Medical Center Freiburg Freiburg Germany

Department of Rheumatology and Clinical Immunology University Medical Center Freiburg Faculty of Medicine University of Freiburg Freiburg Germany

Department of Rheumatology and Immunology Hannover Medical School Hannover Germany

Division of Clinical and Experimental Immunology Institute of Immunology Center for Pathophysiology Infectiology and Immunology Medical University of Vienna Vienna Austria

Division of Molecular Immunology Department of Internal Medicine 3 Nikolaus Fiebiger Zentrum Friedrich Alexander University Erlangen Nürnberg Erlangen 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

Institute of Medical Bioinformatics and Systems Medicine University Medical Center Freiburg Faculty of Medicine University of Freiburg Freiburg Germany

Institute of Pathology Heinrich Heine University and University Hospital of Düsseldorf Düsseldorf Germany

Medical Physics Department Centro Atómico Bariloche Comisión Nacional de Energía Atómica San Carlos de Bariloche Argentina

Pediatric Hematology Immunology and Rheumatology Department University Hospital Necker Enfants Malades Paris France

Primary Immunodeficiencies Unit Department of Pediatrics Research Institute Hospital 12 Octubre Madrid Spain

School of Medicine Complutense University Madrid Spain

Université de Paris Laboratory of Immunogenetics of Pediatric Autoimmune Diseases Imagine Institute INSERM UMR 1163 Paris France

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