Germinal centers: programmed for affinity maturation and antibody diversification

Inducible T cell co-stimulator (ICOS) plays a key role in the differentiation and maintenance of follicular helper T (Tfh) cells and thus germinal center (GC) formation. Previously, our lab showed in a Plasmodium chabaudi infection model that Icos -/- mice were significantly impaired in their ability to form GCs despite a persistent infection and thus a continued antigen (Ag) load. Here, we show that resolution of a primary infection with P. yoelii , was delayed in Icos -/- mice. This phenotype was associated with a reduction in the accumulation of Tfh-like and GC Tfh cells and an early deficiency in Ag-specific antibody (Ab) production. However, Icos -/- mice could form GCs, though they were less frequent in number than in wild-type (WT) mice. Nonetheless, the Ag-specific Abs from Icos -/- mice lacked signs of affinity maturation, suggesting functional defects associated with these GCs. Eventually, these GC structures dissipated more rapidly in Icos -/- mice than in WT mice. Moreover, the ability of Icos -/- mice to form these GC structures is not reliant on the high Ag load associated with P. yoelii infections, as GC formation was preserved in Icos -/- mice treated with atovaquone. Finally, mice were unable to form secondary GCs in the absence of ICOS after re-challenge. Overall, these data demonstrate the necessity of ICOS in the maintenance of Tfh cells, the formation and maintenance of sufficient numbers of functioning GCs, and the ability to generate new GC structures after re-infection with P. yoelii .

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Quantitative modeling of the effect of antigen dosage on B-cell affinity distributions in maturating germinal centers

10.1101/2020.05.22.110585 ◽

2020 ◽

Author(s):

Marco Molari ◽

Klaus Eyer ◽

Jean Baudry ◽

Simona Cocco ◽

Rémi Monasson

Keyword(s):

Germinal Centers ◽

Affinity Maturation ◽

Likelihood Inference ◽

Quantitative Modeling ◽

Dynamical Process ◽

Biological Processes ◽

Cell Affinity ◽

Detailed Mathematical Analysis ◽

Population Affinity ◽

Antibody Population

AbstractAffinity maturation is a complex dynamical process allowing the immune system to generate antibodies capable of recognizing antigens. We introduce a model for the evolution of the distribution of affinities across the antibody population in germinal centers. The model is amenable to detailed mathematical analysis, and gives insight on the mechanisms through which antigen availability controls the rate of maturation and the expansion of the antibody population. It is also capable, upon maximum-likelihood inference of the parameters, to reproduce accurately the distributions of affinities of IgG-secreting cells we measure in mice immunized against Tetanus Toxoid under largely varying conditions (antigen dosage, delay between injections). Both model and experiments show that the average population affinity depends non-monotonically on the antigen dosage. We show that combining quantitative modelling and statistical inference is a concrete way to investigate biological processes underlying affinity maturation (such as selection permissiveness), hardly accessible through measurements.

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Affinity Maturation Is Impaired by Natural Killer Cell Suppression of Germinal Centers

Cell Reports ◽

10.1016/j.celrep.2018.08.075 ◽

2018 ◽

Vol 24 (13) ◽

pp. 3367-3373.e4 ◽

Cited By ~ 20

Author(s):

Carolyn E. Rydyznski ◽

Stacey A. Cranert ◽

Julian Q. Zhou ◽

Heping Xu ◽

Steven H. Kleinstein ◽

...

Keyword(s):

Natural Killer Cell ◽

Natural Killer ◽

Killer Cell ◽

Germinal Centers ◽

Affinity Maturation ◽

Cell Suppression

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The immunoglobulin heavy-chain locus hs3b and hs4 3′ enhancers are dispensable for VDJ assembly and somatic hypermutation

Blood ◽

10.1182/blood-2002-12-3827 ◽

2003 ◽

Vol 102 (4) ◽

pp. 1421-1427 ◽

Cited By ~ 39

Author(s):

Caroline Le Morvan ◽

Eric Pinaud ◽

Catherine Decourt ◽

Armelle Cuvillier ◽

Michel Cogné

Keyword(s):

B Cells ◽

B Cell ◽

Heavy Chain ◽

Somatic Hypermutation ◽

Class Switch Recombination ◽

Immunoglobulin Heavy Chain ◽

Germinal Centers ◽

Affinity Maturation ◽

Class Switch ◽

Endogenous Locus

Abstract The more distal enhancers of the immunoglobulin heavy-chain 3′ regulatory region, hs3b and hs4, were recently demonstrated as master control elements of germline transcription and class switch recombination to most immunoglobulin constant genes. In addition, they were shown to enhance the accumulation of somatic mutations on linked transgenes. Since somatic hypermutation and class switch recombination are tightly linked processes, their common dependency on the endogenous locus 3′ enhancers could be an attractive hypothesis. VDJ structure and somatic hypermutation were analyzed in B cells from mice carrying either a heterozygous or a homozygous deletion of these enhancers. We find that hs3b and hs4 are dispensable both for VDJ assembly and for the occurrence of mutations at a physiologic frequency in the endogenous locus. In addition, we show that cells functionally expressing the immunoglobulin M (IgM) class B-cell receptor encoded by an hs3b/hs4-deficient locus were fully able to enter germinal centers, undergo affinity maturation, and yield specific antibody responses in homozygous mutant mice, where IgG1 antibodies compensated for the defect in other IgG isotypes. By contrast, analysis of Peyer patches from heterozygous animals showed that peanut agglutinin (PNAhigh) B cells functionally expressing the hs3b/hs4-deficient allele were dramatically outclassed by B cells expressing the wild-type locus and normally switching to IgA. This study thus also highlights the role of germinal centers in the competition between B cells for affinity maturation and suggests that membrane IgA may promote recruitment in an activated B-cell compartment, or proliferation of activated B cells, more efficiently than IgM in Peyer patches.

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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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