Mechanisms of selection and differentiation in germinal centers

Germinal centers (GCs) are complex, multicell-type, transient structures that form in secondary lymphatic tissues in response to T cell-dependent stimulation. This process is crucial to the adaptive immune response because it is the source of affinity maturation and long-lived B cell memory. Our previous studies showed that the growth of murine splenic GCs is nonsynchronized, involving broad-volume distributions of individual GCs at any time. This raises the question whether such a thing as a typical GC exists. To address this matter, we acquired large-scale confocal data on GCs throughout the course of the 2-phenyl-5-oxazolone chicken serum albumin-driven primary immune response in BALB/c mice. Semiautomated image analysis of 3457 GC sections revealed that, although there is no typical GC in terms of size, GCs have a typical cellular composition in that the cell ratios of resident T cells, macrophages, proliferating cells, and apoptotic nuclei are maintained during the established phase of the response. Moreover, our data provide evidence that the dark zone (DZ) and light zone (LZ) compartments of GCs are about the same size and led us to estimate that the minimal cell loss rate in GCs is 3% per hour. Furthermore, we found that the population of GC macrophages is larger and more heterogeneous than previously thought, and that despite enrichment of T cells in the LZ, the DZ of murine splenic GCs is not poor in T cells. DZ and LZ differ in the T cell-to-macrophage ratio rather than in the density of T cells.

Section: Immunohistologymentioning

confidence: 99%

mentioning

confidence: 99%

Is There a Typical Germinal Center? A Large-Scale Immunohistological Study on the Cellular Composition of Germinal Centers during the Hapten-Carrier–Driven Primary Immune Response in Mice

Wittenbrink

Klein

Weiser

et al. 2011

“…Selection in peripheral sites, including GC, is based upon a B cell's ability to not only bind foreign Ag, but also to compete in a Darwinian fashion for limited opportunistic binding with accessory cells, including follicular dendritic cells (FDC) and T cells (6,(11)(12)(13)(14)(15)(16)(17)(18). These cells deliver critical life-promoting secondary signals that are essential for continued B cell survival (19 -25).…”

Section: Igh V-region Sequence Does Not Predict the Survival Fate Ofmentioning

confidence: 99%

IgH V-Region Sequence Does Not Predict the Survival Fate of Human Germinal Center B Cells

Jackson

Capra

2005

Germinal center (GC) B cell survival fate is governed in part by the outcome of successful/failed BCR-mediated interactions with accessory cells. However, the extent to which the BCR primary sequence influences such interactions is not fully understood. Over 1000 IgVH4 family cDNAs were sequenced from living (annexin V−) and apoptotic (annexin V+ or from within tingible body macrophages) GC B cell fractions from seven tonsils. Results surprisingly demonstrate that living and dying GC B cells do not significantly differ in IgVH, D, or JH gene segment use; HCDR3 length or positive charge; or mutation frequency. Additionally, equivalent IgH cDNA sequences were identified in both fractions, suggesting that BCR sequence alone is an unreliable predictor of GC B cell survival.

“…They constitute preferential sites for B cell interactions that are crucial for an efficient Ag-elicited humoral immune response. Observations concerning the physiology of the GC have accumulated in the last 50 years (1)(2)(3)(4). A primary GC reaction starts within 3 to 4 days after Ag administration and lasts for ϳ3 wk.…”

mentioning

confidence: 99%

Modelling Two Possible Mechanisms for the Regulation of the Germinal Center Dynamics

Moreira

Faro

2006

Research on the germinal center has tried to unravel the mechanisms that control its dynamics. In this study we focus on the termination of the germinal center reaction, which is still an open problem. We propose two hypothetical biological mechanisms that may be responsible for the control of germinal center dynamics and analyze them through mathematical models. The first one is based on the differentiation of follicular dendritic cells and/or T cells. Interaction of these cells in the differentiated state with germinal center B cells would promote B cell differentiation into memory B cells and Ab-forming cells, ending the germinal center reaction. The second mechanism applies only to a scenario without recycling and consists of the decay of a hypothetical proliferation signal for centroblasts that limits the number of cell divisions. Each of the models makes predictions that can be experimentally tested.