Pten controls B‐cell responsiveness and germinal center reaction by regulating the expression of IgD BCR

• Corinna S Setz ^[3] ; Ahmad Khadour ^[3] ; Valerio Renna ^[3] ; Joseena Iype ^[4] ; Eva Gentner ^[3] ; Xiaocui He ^[1] ; Moumita Datta ^[3] ; Marc Young ^[3] ; Lars Nitschke ^[2] ; Jürgen Wienands ^[5] ; Palash C Maity ^[3] ; Michael Reth ^[1] ; Hassan Jumaa ^[3]
  1. [1] University of Freiburg

     University of Freiburg

     Stadtkreis Freiburg im Breisgau, Alemania

     
  2. [2] University of Erlangen-Nuremberg

     University of Erlangen-Nuremberg

     Kreisfreie Stadt Erlangen, Alemania

     
  3. [3] 1 Institute of Immunology Ulm University Medical Center Ulm Germany
  4. [4] 1 Institute of Immunology Ulm University Medical Center Ulm Germany; 2 Department of Molecular Immunology, Biology III Faculty of Biology Albert‐Ludwigs University of Freiburg Freiburg Germany; 5Present address: Clinical Cytomics Facility University Institute of Clinical Chemistry Inselspital Bern University Hospital Switzerland
  5. [5] 4 Cellular and Molecular Immunology Georg August University Göttingen Göttingen Germany

  Mostrar afiliaciones +
• Localización: EMBO journal: European Molecular Biology Organization, ISSN 0261-4189, Vol. 38, Nº. 11, 2019
• Idioma: inglés
• Enlaces
  • Texto completo
• Resumen

  • In contrast to other B‐cell antigen receptor (BCR) classes, the function of IgD BCR on mature B cells remains largely elusive as mature B cells co‐express IgM, which is sufficient for development, survival, and activation of B cells. Here, we show that IgD expression is regulated by the forkhead box transcription factor FoxO1, thereby shifting the responsiveness of mature B cells towards recognition of multivalent antigen. FoxO1 is repressed by phosphoinositide 3‐kinase (PI3K) signaling and requires the lipid phosphatase Pten for its activation. Consequently, Pten‐deficient B cells expressing knock‐ins for BCR heavy and light chain genes are unable to upregulate IgD. Furthermore, in the presence of autoantigen, Pten‐deficient B cells cannot eliminate the autoreactive BCR specificity by secondary light chain gene recombination. Instead, Pten‐deficient B cells downregulate BCR expression and become unresponsive to further BCR‐mediated stimulation. Notably, we observed a delayed germinal center (GC) reaction by IgD‐deficient B cells after immunization with trinitrophenyl‐ovalbumin (TNP‐Ova), a commonly used antigen for T‐cell‐dependent antibody responses. Together, our data suggest that the activation of IgD expression by Pten/FoxO1 results in mature B cells that are selectively responsive to multivalent antigen and are capable of initiating rapid GC reactions and T‐cell‐dependent antibody responses.