Molecular mechanisms insulating proliferation from genotoxic stress in B lymphocytes

• Published in: Trends in immunology 2023-09, Vol.44 (9), p.668-677
• Main Authors: Wright, Nathaniel E., Mandal, Malay, Clark, Marcus R.
• Format: Article
• Language: English
• Subjects: Animals; B cell; B-Lymphocytes; Cell Proliferation; Chromatin; DNA Damage; Germinal Center; Humans; lymphopoiesis; Mammals; proliferation; somatic mutation
• ISSN: 1471-4906; 1471-4981; 1471-4981
• DOI: 10.1016/j.it.2023.06.010

In mammals, B cells strictly segregate proliferation from somatic mutation as they develop within the bone marrow and then mature through germinal centers (GCs) in the periphery. Failure to do so risks autoimmunity and neoplastic transformation. Recent work has described how B cell progenitors transition between proliferation and mutation via cytokine signaling pathways, epigenetic chromatin regulation, and remodeling of 3D chromatin conformation. We propose a three-zone model of the GC that describes how proliferation and mutation are regulated. Using this model, we consider how recent mechanistic discoveries in B cell progenitors inform models of GC B cell function and reveal fundamental mechanisms underpinning humoral immunity, autoimmunity, and lymphomagenesis. A new three-zone model of the GC reveals large transcriptional and chromatin accessibility differences between murine GC B cells undergoing selection, proliferation, and somatic hypermutation (SHM). GC B cells undergoing proliferation have unique molecular and metabolic programs.Both proliferating and apoptotic murine GC B cells cluster next to tingible body macrophages, suggesting that this is a major checkpoint for removing apoptotic cells before undergoing mitosis that may be important for preventing autoimmunity and lymphomagenesis.The new three-receptor model of B cell development may explain how the IL-7 receptor, pre-B cell receptor, and CXCR4 segregate proliferation from light-chain recombination by transitioning between mutually exclusive states. Parallels between B cell progenitors and the GC suggest that CXCR4 signaling may mediate the transition between proliferation and SHM in the GC.Recent evidence describes how the regulation of cohesin and chromatin topology allows large and rapid changes between the different molecular programs of B cells. These results suggest that cohesin regulation may be a significant mechanism by which GC B cells regulate their proliferation and mutation to prevent oncogenesis. Recent studies support a three-zone model of the germinal center (GC) in which B cells use distinct molecular programs to insulate proliferation from somatic hypermutation. Parallels between how B cell progenitors and GC B cells separate proliferation from mutation demonstrate shared solutions across the B cell lineage using cytokine signaling, epigenetic reordering of chromatin, and regulation of chromatin topology. Understanding these mechanisms might reveal new opportunities to ma