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

• Published in: The EMBO journal Vol. 38; no. 11
• Main Authors: Setz, Corinna S, Khadour, Ahmad, Renna, Valerio, Iype, Joseena, Gentner, Eva, He, Xiaocui, Datta, Moumita, Young, Marc, Nitschke, Lars, Wienands, Jürgen, Maity, Palash C, Reth, Michael, Jumaa, Hassan
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 03.06.2019; Blackwell Publishing Ltd; John Wiley and Sons Inc
• Subjects: 1-Phosphatidylinositol 3-kinase; Anergy; Animals; Antibodies; Antigens; B-cell receptor; B-Lymphocytes - physiology; B‐cell differentiation; Cell activation; Cells, Cultured; Chains; EMBO19; EMBO37; Forkhead Box Protein O1 - physiology; Forkhead protein; FoxO1; FOXO1 protein; Gene expression; Gene Expression Regulation - immunology; Gene rearrangement; Germinal Center - metabolism; Germinal Center - physiology; Germinal centers; immune response; Immunization; Immunoglobulin D; Immunoglobulin D - genetics; Immunoglobulin D - immunology; Immunoglobulin D - metabolism; Immunoglobulin M; Kinases; Lipids; Lymphocytes B; Mice; Mice, Transgenic; Ovalbumin; Pten; PTEN Phosphohydrolase - genetics; PTEN Phosphohydrolase - physiology; PTEN protein; Receptors, Antigen, B-Cell - genetics; Receptors, Antigen, B-Cell - metabolism; Recombination; Signal Transduction - genetics; Signal Transduction - immunology; tolerance; Trinitrophenyl; B‐cell differentiation; Pten; immune response; tolerance; FoxO1
• ISSN: 0261-4189; 1460-2075
• DOI: 10.15252/embj.2018100249

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. Synopsis By activation of Ig gene rearrangement and receptor editing, Pten controls antibody diversity and the development of self‐tolerant B cells. Pten also controls the development of follicular B cellsand their responsiveness towards complex antigen. Pten is required for receptor editing but not for anergy in B cells. Increased IgD BCR expression results in mature B cells that are controlled by soluble antigen whileresponsive to antigencomplexes. Pten activates IgD BCR expression and selective B cell responsiveness through FoxO1. IgD regulates the quality of immune responses by efficiently directing B cells into GC reactions. Graphical Abstract Regulation of PI3‐kinase‐FoxO1 by the lipid phosphatase PTEN is critical for the activation of IgD expression, which is needed for the generation of mature B cells fully responsive to antigen complexes.