AKT activity orchestrates marginal zone B cell development in mice and humans

Eva-Maria Cox; Mohamed El-Behi; Stefanie Ries; Johannes F Vogt; Vivien Kohlhaas; Thomas Michna; Benoît Manfroi; Mona Al-Maarri; Florian Wanke; Boaz Tirosh; Corinne Pondarre; Harry Lezeau; Nir Yogev; Romy Mittenzwei; Marc Descatoire; Sandra Weller; Jean-Claude Weill; Claude-Agnès Reynaud; Pierre Boudinot; Luc Jouneau; Stefan Tenzer; Ute Distler; Anne Rensing-Ehl; Christoph König; Julian Staniek; Marta Rizzi; Aude Magérus; Frederic Rieux-Laucat; F Thomas Wunderlich; Nadine Hövelmeyer; Simon Fillatreau

doi:10.1016/j.celrep.2023.112378

AKT activity orchestrates marginal zone B cell development in mice and humans

Cell Rep. 2023 Apr 25;42(4):112378. doi: 10.1016/j.celrep.2023.112378. Epub 2023 Apr 14.

Authors

Eva-Maria Cox¹, Mohamed El-Behi², Stefanie Ries³, Johannes F Vogt¹, Vivien Kohlhaas⁴, Thomas Michna⁵, Benoît Manfroi², Mona Al-Maarri⁴, Florian Wanke¹, Boaz Tirosh⁶, Corinne Pondarre⁷, Harry Lezeau⁷, Nir Yogev⁸, Romy Mittenzwei¹, Marc Descatoire⁹, Sandra Weller², Jean-Claude Weill², Claude-Agnès Reynaud², Pierre Boudinot¹⁰, Luc Jouneau¹⁰, Stefan Tenzer¹¹, Ute Distler⁵, Anne Rensing-Ehl¹², Christoph König¹³, Julian Staniek¹⁴, Marta Rizzi¹⁵, Aude Magérus¹⁶, Frederic Rieux-Laucat¹⁶, F Thomas Wunderlich⁴, Nadine Hövelmeyer¹⁷, Simon Fillatreau¹⁸

Affiliations

¹ Institute for Molecular Medicine Mainz, University Hospital of Mainz, 55131 Mainz, Germany.
² Institut Necker Enfants Malades, INSERM U1151-CNRS UMR 8253, 156-160, rue de Vaugirard, 75015 Paris, France.
³ Deutsches Rheuma-Forschungszentrum, a Leibniz Institute, 10117 Berlin, Germany.
⁴ Max Planck Institute for Metabolism Research Cologne, 50931 Cologne, Germany; Institute for Genetics, University of Cologne, 50931 Cologne, Germany; Cologne Excellence Cluster on Cellular Stress Responses in Aging-associated Diseases (CECAD), 50931 Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), 50931 Cologne, Germany; Center for Endocrinology, Diabetes and Preventive Medicine (CEDP) Cologne, 50931 Cologne, Germany.
⁵ Institute for Immunology, University Medical Centre of the Johannes-Gutenberg University Mainz, Mainz, Germany.
⁶ The Hebrew University of Jerusalem, Institute for Drug Research, Jerusalem, Israel.
⁷ Service de Pédiatrie Générale, Centre de Référence de la Drépanocytose, Centre Intercommunal de Créteil, Créteil, France; Inserm U955, Université Paris XII, Créteil, France.
⁸ Faculty of Medicine, Department of Dermatology, University of Cologne, 50931 Cologne, Germany.
⁹ Laboratory of Immune Inherited Disorders, Department of Immunology and Allergology Lausanne Hospital CHUV, Lausanne, Switzerland.
¹⁰ Université Paris-Saclay, INRAE, UVSQ, VIM, 78350 Jouy-en-Josas, France.
¹¹ Institute for Immunology, University Medical Centre of the Johannes-Gutenberg University Mainz, Mainz, Germany; Research Centre for Immunotherapy (FZI), University Medical Center of the Johannes-Gutenberg University Mainz, Mainz, Germany; Helmholtz Institute for Translational Oncology Mainz (HI-TRON Mainz), Mainz, Germany.
¹² Institute for Immunodeficiency, Center for Chronic Immunodeficiency, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
¹³ Institute for Immunodeficiency, Center for Chronic Immunodeficiency, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany; University of Freiburg, Faculty of Biology, Schaenzlestrasse 1, 79104 Freiburg, Germany.
¹⁴ Department of Rheumatology and Clinical Immunology, University Medical Center Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
¹⁵ Department of Rheumatology and Clinical Immunology, University Medical Center Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany; Center for Chronic Immunodeficiency, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany; Division of Clinical and Experimental Immunology, Institute of Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria.
¹⁶ Université Paris Cité, Institut Imagine, Laboratory of Immunogenetics of Pediatric Autoimmune Diseases, INSERM UMR 1163, 75015 Paris, France.
¹⁷ Institute for Molecular Medicine Mainz, University Hospital of Mainz, 55131 Mainz, Germany; Research Centre for Immunotherapy (FZI), University Medical Center of the Johannes-Gutenberg University Mainz, Mainz, Germany. Electronic address: [email protected].
¹⁸ Institut Necker Enfants Malades, INSERM U1151-CNRS UMR 8253, 156-160, rue de Vaugirard, 75015 Paris, France; Université de Paris Cité, Paris Descartes, Faculté de Médecine, Paris, France; AP-HP, Hôpital Necker Enfants Malades, Paris, France. Electronic address: [email protected].

PMID: 37060566
DOI: 10.1016/j.celrep.2023.112378

Abstract

The signals controlling marginal zone (MZ) and follicular (FO) B cell development remain incompletely understood. Here, we show that AKT orchestrates MZ B cell formation in mice and humans. Genetic models that increase AKT signaling in B cells or abolish its impact on FoxO transcription factors highlight the AKT-FoxO axis as an on-off switch for MZ B cell formation in mice. In humans, splenic immunoglobulin (Ig) D⁺CD27⁺ B cells, proposed as an MZ B cell equivalent, display higher AKT signaling than naive IgD⁺CD27^- and memory IgD^-CD27⁺ B cells and develop in an AKT-dependent manner from their precursors in vitro, underlining the conservation of this developmental pathway. Consistently, CD148 is identified as a receptor indicative of the level of AKT signaling in B cells, expressed at a higher level in MZ B cells than FO B cells in mice as well as humans.

Keywords: AKT; ALPS; B cells; CD148; CP: Developmental biology; CP: Immunology; FoxO1; NOTCH2; marginal zone B cells.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
B-Lymphocytes*
Humans
Lymphoid Tissue
Mice
Proto-Oncogene Proteins c-akt*
Signal Transduction
Spleen

Substances

Proto-Oncogene Proteins c-akt