Germinal center entry not selection of B cells is controlled by peptide-MHCII complex density

Both rapid B-cell proliferation and programmed cell death (PCD) occur during the differentiation and selection of B cells within the germinal center. To help elucidate the role of Bcl-x in B-cell antigen selection and PCD within the germinal center, we examined its expression in defined B-cell populations and by immunochemistry of tonsil tissue. Purified B-cell fractions enriched for centrocytes express high amounts of Bcl-x and relatively low amounts of Bcl-2, whereas fractions enriched for centroblasts lack significant levels of both proteins. Consistent with this observation, immunocytochemistry localized Bcl-x within cells scattered throughout the germinal center. Stimulation of tonsil B cells with either CD40 or Staphylococcus aureus Cowan increase bcl-x mRNA and protein levels. Treatment of a cell line with a germinal center phenotype (RAMOS) or the tonsillar B-cell centroblast fraction with CD40 rapidly increased Bcl-x levels and partially rescued B cells from PCD. These data suggest that Bcl-x rather than Bcl-2 may rescue centrocytes during selection in the germinal center.

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Negative selection of human germinal center B cells by prolonged BCR cross-linking.

Journal of Experimental Medicine ◽

10.1084/jem.183.5.2075 ◽

1996 ◽

Vol 183 (5) ◽

pp. 2075-2085 ◽

Cited By ~ 51

Author(s):

L Galibert ◽

N Burdin ◽

C Barthélémy ◽

G Meffre ◽

I Durand ◽

...

Keyword(s):

Cell Differentiation ◽

B Cells ◽

B Cell ◽

B Lymphocytes ◽

Germinal Center ◽

B Lymphocyte ◽

Calcium Flux ◽

Cross Linking ◽

B Cell Differentiation ◽

Selection Of

The antigen receptors on T and B lymphocytes can transduce both agonist and antagonist signals leading either to activation/survival or anergy/death. The outcome of B lymphocyte antigen receptor (BCR) triggering depends upon multiple parameters which include (a) antigen concentration and valency, (b) duration of BCR occupancy, (c) receptor affinity, and (d) B cell differentiation stages. Herein, using anti-immunoglobulin kappa and lambda light chain antibodies, we analyzed the response of human naive, germinal center (GC) or memory B cells to BCR cross-linking regardless of heavy chain Ig isotype or intrinsic BCR specificity. We show that after CD40-activation, anti-BCR (kappa + gamma) can elicit an intracellular calcium flux on both GC and non-GC cells. However, prolonged BCR cross-linking induces death of CD40-activated GC B cells but enhances proliferation of naive or memory cells. Anti-kappa antibody only kills kappa + GC B cells without affecting surrounding gamma + GC B cells, thus demonstrating that BCR-mediated killing of GC B lymphocytes is a direct effect that does not involve a paracrine mechanism. BCR-mediated killing of CD40-activated GC B cells could be partially antagonized by the addition of IL-4. Moreover, in the presence of IL-4, prestimulation through CD40 could prevent subsequent anti-Ig-mediated cell death, suggesting a specific role of this combination in selection of GC B cells. This report provides evidence that in human, susceptibility to BCR killing is regulated along peripheral B cell differentiation pathway.

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A mechanism of T cell dependent selection of antigen engaged Germinal Center B cells

10.1101/061879 ◽

2016 ◽

Author(s):

Vinod Krishna ◽

Kurtis E. Bachman

Keyword(s):

T Cell ◽

B Cells ◽

B Cell ◽

Germinal Center ◽

Peripheral Tolerance ◽

B Cell Tolerance ◽

Germinal Center Reaction ◽

Dark Zone ◽

T Cell Help ◽

Selection Of

A model of B cell affinity selection is proposed, and an explanation of peripheral tolerance mechanisms through antibody repertoire editing is presented. We show that affinity discrimination between B cells is driven by a competition between obtaining T cell help and removal of B cells from the light zone, either through apoptosis or by a return to the dark zone of germinal centers. We demonstrate that this mechanism also allows for the negative selection of self reactive B cells and maintenance of B cell tolerance during the germinal center reaction. Finally, we demonstrate that clonal expansion upon return to the germinal center dark zone amplifies differences in the antigen affinity of B cells that survive the light zone.

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T Cells in the Selection of Germinal Center B Cells

Chemical Immunology and Allergy - Human B Cell Populations ◽

10.1159/000058676 ◽

1997 ◽

pp. 27-44 ◽

Cited By ~ 8

Author(s):

M. Casamayor-Palleja ◽

A. Gulbranson-Judge ◽

I.C.M. MacLennan

Keyword(s):

T Cells ◽

B Cells ◽

Germinal Center ◽

Selection Of ◽

Germinal Center B Cells

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Antigen-driven B cell differentiation in vivo.

Journal of Experimental Medicine ◽

10.1084/jem.178.1.295 ◽

1993 ◽

Vol 178 (1) ◽

pp. 295-307 ◽

Cited By ~ 216

Author(s):

M G McHeyzer-Williams ◽

M J McLean ◽

P A Lalor ◽

G J Nossal

Keyword(s):

B Cells ◽

Somatic Mutation ◽

Germinal Center ◽

Somatic Hypermutation ◽

Hypervariable Region ◽

Germinal Centers ◽

B Cell Differentiation ◽

The One ◽

Selection Of

The secretion of specific antibodies and the development of somatically mutated memory B cells in germinal centers are consequences of T cell-dependent challenge with the hapten (4-hydroxy-3-nitrophenyl)acetyl (NP). Using six-parameter flow cytometry and single cell molecular analysis we can directly monitor the extent of somatic hypermutation in individual responsive (isotype switched) antigen-specific B cells. The current study provides a direct quantitative assessment of recruitment into the antibody-secreting compartment on the one hand, and the germinal center pathway to memory on the other. Cellular expansion in both compartments is exponential and independent during the first week after challenge. The first evidence of somatic mutation, towards the end of the first week, was restricted to the germinal center pathway. Furthermore, germinal center cells express a significantly shorter third hypervariable region (CDR3), even when unmutated, than their antibody-secreting counterparts, suggesting a secondary selection event may occur at the bifurcation of these two pathways in vivo. By the end of the second week, the majority of mutated clones express a shorter CDR3 and affinity-increasing mutations as evidence of further selection after somatic mutation. These data provide evidence for substantial proliferation within germinal centers before the initiation of somatic mutation and the subsequent selection of a significant frequency of mutated clonotypes into the memory compartment.

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Germinal center B cells separate signals for selection and division like compact discs

10.1101/2020.01.29.925479 ◽

2020 ◽

Author(s):

Michael Meyer-Hermann

Keyword(s):

B Cells ◽

B Cell ◽

Germinal Center ◽

Cell Selection ◽

Audio Signals ◽

Common Concept ◽

Global Understanding ◽

Fate Decision ◽

Concept Of Information ◽

Selection Of

SummarySelection of B cells in germinal center (GC) reactions is pivotal to the generation of high affinity antibodies and memory B cells. Knowledge about B cell selection is limited to individual interactions and lacks global understanding. Here, seemingly contradictory experiments are unified in a common concept by separation of signals for the frequency of fate decision from the strength of cell division, which can then be controlled independently, similar to the separation of frequency and amplitude in digital audio signals. Based on this concept of information processing, three theories of B cell selection are developed that can be distinguish by predicted experiments drawn from computer simulations. Understanding encoding of information in molecular states is critical for targeted immune interventions.

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