Cell cycle-associated CXCR4 expression in germinal center B cells and its implications on affinity maturation
- Author(s)
- Weber, TS;
- Journal Title
- Frontiers in Immunology
- Publication Type
- Journal Article
- Abstract
- Adaptation of antibody-mediated immunity occurs in germinal centers (GC). It is where affinity maturation, class switching, memory and plasma cell differentiation synergize to generate specific high-affinity antibodies that aid both to clear and protect against reinfection of invading pathogens. Within GCs, light and dark zone are two compartments instrumental in regulating this process, by segregating T cell-dependent selection and differentiation from generation of GC B cells bearing hypermutated antigen receptors. Spatial segregation of GC B cells into the two zones relies on the chemokine receptor CXCR4, with textbooks attributing high and low expression to a dark and light zone phenotype. Interestingly, this bipolarity is not reflected in the CXCR4 expression profile of GC B cells, which is highly variable and unimodal, indicating a continuum of intermediate CXCR4 levels rather than a binary dark or light zone phenotype. Here, analysis of published BrdU pulse-chase data reveals that throughout cell cycle, average CXCR4 expression in GC B cells steadily increases close to twofold, scaling with cell surface area. CXCR4 expression in recently divided GC B cells in G0/G1 or early S phase shows intermediate levels compared to cells in G2M phase, consistent with their smaller size. The lowest number of CXCR4 receptors are displayed by relatively aged GC B cells in G0/G1 or early S phase. The latter, upon progressing through S phase, however, ramp up relative CXCR4 expression twice as much as recently divided cells. Twelve hours after the BrdU pulse, labeled GC B cells, while initially in S phase, are desynchronized in terms of cell cycle and match the CXCR4 profile of unlabeled cells. A model is discussed in which CXCR4 expression in GC B cell increases with cell cycle and cell surface area, with highest levels in G2 and M phase, coinciding with GC B cell receptor signaling in G2 and immediately preceding activation-induced cytidine deaminase (AID) activity in early G1. In the model, GC B cells compete for CXCL12 expression on the basis of their CXCR4 expression, gaining a relative advantage as they progress in cell cycle, but loosing the advantage at the moment they divide.
- Publisher
- Frontiers Media
- Research Division(s)
- Molecular Medicine
- PubMed ID
- 29951060
- Publisher's Version
- https://doi.org/10.3389/fimmu.2018.01313
- Open Access at Publisher's Site
https://doi.org/10.3389/fimmu.2018.01313- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2018-07-09 02:45:06
Last Modified: 2018-07-09 03:03:58