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 JouneauStefan Tenzer, Ute Distler, Anne Rensing-Ehl, Christoph König, Julian Staniek, Marta Rizzi, Aude Magérus, Frederic Rieux-Laucat, F. Thomas Wunderlich, Nadine Hövelmeyer*, Simon Fillatreau*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

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 IgDCD27+ 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.

Original languageAmerican English
Article number112378
Pages (from-to)1-24
JournalCell Reports
Volume42
Issue number4
DOIs
StatePublished - 25 Apr 2023

Bibliographical note

Funding Information:
We thank J. Kirsch, H. Schliemann, the Regine von Ramin Laboratory (DRFZ), Petra Adams-Quack and Elena Zurkowski (IMM, Mainz), and Michael Dussiot (IMAGINE) for excellent technical help. We thank E. Six and I. André (IMAGINE) for the OP9 and OP9-DLL1 cell lines. We thank V. Asnafi and E. Macintyre (INEM) for REC-1 cells. The N.H. lab was supported by the Fritz Thyssen Foundation, AZ 10.13.2.173 and by the DFG grant HO4440/1-1, HO4440/1-2, project number 318346496, SFB1292/2 TP20, and the Research Center Immunology (FZI). The S.F. lab is supported by ERC PREG-LAB 647696, AXA Chair Translational Immunology, Agence Nationale de la Recherche (ANR-16-CE18-0007-01), Chair of Excellence (Université Sorbonne Paris Cité). M.R. is supported by the DFG (SFB1160, B02). F.R.L. was funded by the Institut National de la Santé et de la Recherche Médicale (Inserm), the French government (managed by French National Research Agency [Agence Nationale de la Recherche] through the Investissements d'avenir program [Institut Hospitalo-Universitaire Imagine, grant reference, ANR-10-IAHU-01; Recherche Hospitalo-Universitaire, grant reference, ANR-18-RHUS-0010]), and other grants from the Agence National de la Recherche (ANR-18-CE17-0001 Action), the Fondation pour la Recherche Médicale (grant reference, Equipe FRM EQU202103012670). E.M.C. M.E.B. S.R. J.F.V. V.K. T.M. B.M. M.A.M. F.W. B.T. C.P. H.L. N.Y. R.M. M.D. S.W. L.J. S.T. U.D. A.R.E. C.K. J.S. A.M. and F.T.W. performed experiments and provided reagents. P.B. J.C.W. C.A.R. F.R.L. and M.R. designed experiments and supervised data analysis. N.H. and S.F. designed the project, analyzed data, and wrote the manuscript. The authors declare no competing interests.

Funding Information:
We thank J. Kirsch, H. Schliemann, the Regine von Ramin Laboratory (DRFZ), Petra Adams-Quack and Elena Zurkowski (IMM, Mainz), and Michael Dussiot (IMAGINE) for excellent technical help. We thank E. Six and I. André (IMAGINE) for the OP9 and OP9-DLL1 cell lines. We thank V. Asnafi and E. Macintyre (INEM) for REC-1 cells. The N.H. lab was supported by the Fritz Thyssen Foundation , AZ 10.13.2.173 and by the DFG grant HO4440/1-1 , HO4440/1-2 , project number 318346496 , SFB1292/2 TP20 , and the Research Center Immunology ( FZI ). The S.F. lab is supported by ERC PREG-LAB 647696 , AXA Chair Translational Immunology, Agence Nationale de la Recherche ( ANR-16-CE18-0007-01 ), Chair of Excellence ( Université Sorbonne Paris Cité ). M.R. is supported by the DFG ( SFB1160 , B02 ). F.R.L. was funded by the Institut National de la Santé et de la Recherche Médicale ( Inserm ), the French government (managed by French National Research Agency [ Agence Nationale de la Recherche ] through the Investissements d’avenir program [ Institut Hospitalo-Universitaire Imagine , grant reference, ANR-10-IAHU-01 ; Recherche Hospitalo-Universitaire , grant reference, ANR-18-RHUS-0010 ]), and other grants from the Agence National de la Recherche ( ANR-18-CE17-0001 Action), the Fondation pour la Recherche Médicale (grant reference, Equipe FRM EQU202103012670 ).

Publisher Copyright:
© 2023

Keywords

  • AKT
  • ALPS
  • B cells
  • CD148
  • CP: Developmental biology
  • CP: Immunology
  • FoxO1
  • NOTCH2
  • marginal zone B cells

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