B Cell Receptor and CD40 Signaling Are Rewired for Synergistic Induction of the c-Myc Transcription Factor in Germinal Center B Cells

• Published in: Immunity (Cambridge, Mass.) Vol. 48; no. 2; pp. 313 - 326.e5
• Main Authors: Luo, Wei, Weisel, Florian, Shlomchik, Mark J.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 20.02.2018; Elsevier Limited
• Subjects: Affinity; affinity maturation; Akt; Animals; Antigens; B cell; B cell receptor; c-Myc protein; CD40; CD40 antigen; CD40 Antigens - physiology; Cell cycle; Cell survival; Clonal selection; Forkhead Box Protein O1 - physiology; Foxo1; FOXO1 protein; germinal center; Germinal Center - immunology; Germinal centers; Helper cells; Kinases; Ligands; Light; Lymphocyte receptors; Lymphocytes; Lymphocytes B; Lymphocytes T; MAP Kinase Signaling System - physiology; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Myc; Myc protein; Neurons; NF-kappa B - physiology; NF-κB protein; Phosphatidylinositol 3-Kinases - physiology; Positive selection; Proto-Oncogene Proteins c-akt - physiology; Proto-Oncogene Proteins c-myc - biosynthesis; Receptors, Antigen, B-Cell - physiology; Reentry; Signal Transduction - physiology; Signaling; Survival; Syk; Syk Kinase - physiology; Transcription factors; B cell; CD40; Syk; Myc; affinity maturation; germinal center; Akt; B cell receptor; Foxo1
• ISSN: 1074-7613; 1097-4180; 1097-4180
• DOI: 10.1016/j.immuni.2018.01.008

Positive selection of germinal center (GC) B cells is driven by B cell receptor (BCR) affinity and requires help from follicular T helper cells. The transcription factors c-Myc and Foxo1 are critical for GC B cell selection and survival. However, how different affinity-related signaling events control these transcription factors in a manner that links to selection is unknown. Here we showed that GC B cells reprogram CD40 and BCR signaling to transduce via NF-κB and Foxo1, respectively, whereas naive B cells propagate both signals downstream of either receptor. Although either BCR or CD40 ligation induced c-Myc in naive B cells, both signals were required to highly induce c-Myc, a critical mediator of GC B cell survival and cell cycle reentry. Thus, GC B cells rewire their signaling to enhance selection stringency via a requirement for both antigen receptor- and T cell-mediated signals to induce mediators of positive selection. [Display omitted] •In GC B cells, CD40 signals via NF-κB but not PI3K, while BCR does not activate NF-κB•Weak BCR signals in GC B cells propagate to Akt-dependent phosphorylation of Foxo1•In GC B cells, both CD40 and BCR signals are required to synergistically induce c-Myc•Combined CD40 and BCR signals induce p-S6 in GC B cells, permitting cell cycle entry Luo et al. show that CD40 and BCR signaling in GC B cells is rewired to control very different pathways, and both signals are required for optimal induction of c-Myc, suggesting a mechanism of signaling-directed positive selection of GC B cells.