Taking Advantage: High-Affinity B Cells in the Germinal Center Have Lower Death Rates, but Similar Rates of Division, Compared to Low-Affinity Cells

Protective antibody responses to vaccination or infection depend on affinity maturation, a process by which high-affinity germinal center (GC) B cells are selected on the basis of their ability to bind, gather, and present antigen to T follicular helper (Tfh) cells. Here, we show that human GC B cells have intrinsically higher-affinity thresholds for both B cell antigen receptor (BCR) signaling and antigen gathering as compared with naïve B cells and that these functions are mediated by distinct cellular structures and pathways that ultimately lead to antigen affinity– and Tfh cell–dependent differentiation to plasma cells. GC B cells bound antigen through highly dynamic, actin- and ezrin-rich pod-like structures that concentrated BCRs. The behavior of these structures was dictated by the intrinsic antigen affinity thresholds of GC B cells. Low-affinity antigens triggered continuous engagement and disengagement of membrane-associated antigens, whereas high-affinity antigens induced stable synapse formation. The pod-like structures also mediated affinity-dependent antigen internalization by unconventional pathways distinct from those of naïve B cells. Thus, intrinsic properties of human GC B cells set thresholds for affinity selection.

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Germinal Centers without T Cells

Journal of Experimental Medicine ◽

10.1084/jem.191.3.485 ◽

2000 ◽

Vol 191 (3) ◽

pp. 485-494 ◽

Cited By ~ 202

Author(s):

Carola García de Vinuesa ◽

Matthew C. Cook ◽

Jennifer Ball ◽

Marion Drew ◽

Yvonne Sunners ◽

...

Keyword(s):

T Cells ◽

B Cells ◽

B Cell ◽

Germinal Center ◽

High Efficiency ◽

Germinal Centers ◽

Affinity Maturation ◽

High Affinity ◽

Safe Mechanism ◽

Germinal Center Formation

Germinal centers are critical for affinity maturation of antibody (Ab) responses. This process allows the production of high-efficiency neutralizing Ab that protects against virus infection and bacterial exotoxins. In germinal centers, responding B cells selectively mutate the genes that encode their receptors for antigen. This process can change Ab affinity and specificity. The mutated cells that produce high-affinity Ab are selected to become Ab-forming or memory B cells, whereas cells that have lost affinity or acquired autoreactivity are eliminated. Normally, T cells are critical for germinal center formation and subsequent B cell selection. Both processes involve engagement of CD40 on B cells by T cells. This report describes how high-affinity B cells can be induced to form large germinal centers in response to (4-hydroxy-3-nitrophenyl) acetyl (NP)-Ficoll in the absence of T cells or signaling through CD40 or CD28. This requires extensive cross-linking of the B cell receptors, and a frequency of antigen-specific B cells of at least 1 in 1,000. These germinal centers abort dramatically at the time when mutated high-affinity B cells are normally selected by T cells. Thus, there is a fail-safe mechanism against autoreactivity, even in the event of thymus-independent germinal center formation.

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Co-stimulatory function in primary germinal center responses: CD40 and B7 are required on distinct antigen-presenting cells

Journal of Experimental Medicine ◽

10.1084/jem.20161955 ◽

2017 ◽

Vol 214 (9) ◽

pp. 2795-2810 ◽

Cited By ~ 25

Author(s):

Masashi Watanabe ◽

Chiharu Fujihara ◽

Andrea J. Radtke ◽

Y. Jeffrey Chiang ◽

Sumeena Bhatia ◽

...

Keyword(s):

T Cells ◽

B Cells ◽

Germinal Center ◽

Helper T Cells ◽

Vaccine Responses ◽

High Affinity ◽

Prevailing Paradigm ◽

Follicular Helper ◽

Cd40 Expression ◽

Antigen Presenting

T cell–dependent germinal center (GC) responses require coordinated interactions of T cells with two antigen-presenting cell (APC) populations, B cells and dendritic cells (DCs), in the presence of B7- and CD40-dependent co-stimulatory pathways. Contrary to the prevailing paradigm, we found unique cellular requirements for B7 and CD40 expression in primary GC responses to vaccine immunization with protein antigen and adjuvant: B7 was required on DCs but was not required on B cells, whereas CD40 was required on B cells but not on DCs in the generation of antigen-specific follicular helper T cells, antigen-specific GC B cells, and high-affinity class-switched antibody production. There was, in fact, no requirement for coexpression of B7 and CD40 on the same cell in these responses. Our findings support a substantially revised model for co-stimulatory function in the primary GC response, with crucial and distinct contributions of B7- and CD40-dependent pathways expressed by different APC populations and with important implications for understanding how to optimize vaccine responses or limit autoimmunity.

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Bhlhe40: Gatekeeper of the GC

Journal of Experimental Medicine ◽

10.1084/jem.20212333 ◽

2021 ◽

Vol 219 (2) ◽

Author(s):

Stephen L. Nutt ◽

Julie Tellier

Keyword(s):

B Cells ◽

Germinal Center ◽

T Follicular Helper Cells ◽

High Affinity ◽

Helper Cells ◽

Follicular Helper

The generation of high-affinity antibodies in the germinal center (GC) requires interplay between GC B cells and T follicular helper cells. Rauschmeier et al. (2021. J. Exp. Med.https://doi.org/10.1084/jem.20211406) report that Bhlhe40 restrains GC output through distinct regulatory roles in both arms of the response.

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