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Germinal centers without T cells.

de Vinuesa CG, Cook MC, Ball J, Drew M, Sunners Y, Cascalho M, Wabl M, Klaus GG, MacLennan IC - J. Exp. Med. (2000)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Medical Research Council Centre for Immune Regulation, University of Birmingham, Birmingham B15 2TT, United Kingdom.

ABSTRACT
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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The formation and demise of germinal centers in QM mouse splenic follicles in response to NP-Ficoll. (a and b) Sections of spleen from nonimmunized QM mice. NP-specific cells (blue) in the follicular mantle and marginal zones surround a small germinal center, which is not NP-specific (a) and contains normal numbers of CD3+ T cells (blue, b). Red-stained nuclei of cells in the germinal center have taken up BrdU, given to mice 2 h before the spleen was taken. (c and d) Sections of spleen from QM mice after intraperitoneal immunization with NP-Ficoll. Large T cell–independent germinal centers are PNA+ (blue, c) and contain few CD3+ T cells (blue, d). (e and f) Sections of spleen from QM nude mouse chimeras 4 d after intraperitoneal immunization with NP-Ficoll. Germinal centers are PNA+ (blue, e) and contain NP-binding B cells (blue, f). Heavy blue staining in the red pulp and around the central arteriole are NP-specific plasmablasts. (g) TUNEL staining (blue) of a germinal center in spleen from a QM mouse 5 d after intraperitoneal immunization with NP-Ficoll. (h) Section of spleen from a QM mouse in which no germinal centers can be seen 6 d after intraperitoneal immunization with NP-Ficoll. G, germinal center; T, T zone; R, red pulp.
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Figure 1: The formation and demise of germinal centers in QM mouse splenic follicles in response to NP-Ficoll. (a and b) Sections of spleen from nonimmunized QM mice. NP-specific cells (blue) in the follicular mantle and marginal zones surround a small germinal center, which is not NP-specific (a) and contains normal numbers of CD3+ T cells (blue, b). Red-stained nuclei of cells in the germinal center have taken up BrdU, given to mice 2 h before the spleen was taken. (c and d) Sections of spleen from QM mice after intraperitoneal immunization with NP-Ficoll. Large T cell–independent germinal centers are PNA+ (blue, c) and contain few CD3+ T cells (blue, d). (e and f) Sections of spleen from QM nude mouse chimeras 4 d after intraperitoneal immunization with NP-Ficoll. Germinal centers are PNA+ (blue, e) and contain NP-binding B cells (blue, f). Heavy blue staining in the red pulp and around the central arteriole are NP-specific plasmablasts. (g) TUNEL staining (blue) of a germinal center in spleen from a QM mouse 5 d after intraperitoneal immunization with NP-Ficoll. (h) Section of spleen from a QM mouse in which no germinal centers can be seen 6 d after intraperitoneal immunization with NP-Ficoll. G, germinal center; T, T zone; R, red pulp.

Mentions: When QM mice are immunized intraperitoneally with 30 μg of the polysaccharide antigen NP-Ficoll, they form germinal centers in the spleen (Fig. 1, a–d). These germinal centers are large and can be found in every follicle, but contain very few T cells (Fig. 1c and Fig. d). The phenotype of B cells in NP-Ficoll–induced germinal centers is indistinguishable from germinal centers induced by conventional protein antigen 1226. They stain with PNA, downregulate IgD and B220, and express Bcl-6. The large size and paucity of T cells contrast with background germinal centers seen in QM mice. The background germinal centers are not NP specific; they are small, and contain normal numbers of T cells (Fig. 1, a and b).


Germinal centers without T cells.

de Vinuesa CG, Cook MC, Ball J, Drew M, Sunners Y, Cascalho M, Wabl M, Klaus GG, MacLennan IC - J. Exp. Med. (2000)

The formation and demise of germinal centers in QM mouse splenic follicles in response to NP-Ficoll. (a and b) Sections of spleen from nonimmunized QM mice. NP-specific cells (blue) in the follicular mantle and marginal zones surround a small germinal center, which is not NP-specific (a) and contains normal numbers of CD3+ T cells (blue, b). Red-stained nuclei of cells in the germinal center have taken up BrdU, given to mice 2 h before the spleen was taken. (c and d) Sections of spleen from QM mice after intraperitoneal immunization with NP-Ficoll. Large T cell–independent germinal centers are PNA+ (blue, c) and contain few CD3+ T cells (blue, d). (e and f) Sections of spleen from QM nude mouse chimeras 4 d after intraperitoneal immunization with NP-Ficoll. Germinal centers are PNA+ (blue, e) and contain NP-binding B cells (blue, f). Heavy blue staining in the red pulp and around the central arteriole are NP-specific plasmablasts. (g) TUNEL staining (blue) of a germinal center in spleen from a QM mouse 5 d after intraperitoneal immunization with NP-Ficoll. (h) Section of spleen from a QM mouse in which no germinal centers can be seen 6 d after intraperitoneal immunization with NP-Ficoll. G, germinal center; T, T zone; R, red pulp.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2195827&req=5

Figure 1: The formation and demise of germinal centers in QM mouse splenic follicles in response to NP-Ficoll. (a and b) Sections of spleen from nonimmunized QM mice. NP-specific cells (blue) in the follicular mantle and marginal zones surround a small germinal center, which is not NP-specific (a) and contains normal numbers of CD3+ T cells (blue, b). Red-stained nuclei of cells in the germinal center have taken up BrdU, given to mice 2 h before the spleen was taken. (c and d) Sections of spleen from QM mice after intraperitoneal immunization with NP-Ficoll. Large T cell–independent germinal centers are PNA+ (blue, c) and contain few CD3+ T cells (blue, d). (e and f) Sections of spleen from QM nude mouse chimeras 4 d after intraperitoneal immunization with NP-Ficoll. Germinal centers are PNA+ (blue, e) and contain NP-binding B cells (blue, f). Heavy blue staining in the red pulp and around the central arteriole are NP-specific plasmablasts. (g) TUNEL staining (blue) of a germinal center in spleen from a QM mouse 5 d after intraperitoneal immunization with NP-Ficoll. (h) Section of spleen from a QM mouse in which no germinal centers can be seen 6 d after intraperitoneal immunization with NP-Ficoll. G, germinal center; T, T zone; R, red pulp.
Mentions: When QM mice are immunized intraperitoneally with 30 μg of the polysaccharide antigen NP-Ficoll, they form germinal centers in the spleen (Fig. 1, a–d). These germinal centers are large and can be found in every follicle, but contain very few T cells (Fig. 1c and Fig. d). The phenotype of B cells in NP-Ficoll–induced germinal centers is indistinguishable from germinal centers induced by conventional protein antigen 1226. They stain with PNA, downregulate IgD and B220, and express Bcl-6. The large size and paucity of T cells contrast with background germinal centers seen in QM mice. The background germinal centers are not NP specific; they are small, and contain normal numbers of T cells (Fig. 1, a and b).

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Medical Research Council Centre for Immune Regulation, University of Birmingham, Birmingham B15 2TT, United Kingdom.

ABSTRACT
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.

Show MeSH
Related in: MedlinePlus