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Aiolos is required for the generation of high affinity bone marrow plasma cells responsible for long-term immunity.

Cortés M, Georgopoulos K - J. Exp. Med. (2004)

Bottom Line: Lack of Aiolos does not alter expression of any of the previously described factors required for general plasma cell differentiation.No defect in somatic hypermutation, the generation of memory B cells, or short-lived high affinity plasma cells in the spleen was observed upon rechallenge.These studies support a model by which the high affinity plasma cell population in the BM undergoes a unique differentiation program that is dependent on Aiolos.

View Article: PubMed Central - PubMed

Affiliation: Cutaneous Biology Research Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA.

ABSTRACT
Antigenic encounter generates long-term immunity sustained by long-lived high affinity plasma cells resident in the bone marrow (BM). Here we show that the Ikaros family member, Aiolos, is specifically required for the generation of these plasma cells. Failure to generate high affinity plasma cells in the BM and to sustain serum antibody titers is apparent after both primary and secondary immunization of Aiolos(-)(/)(-) mice with a range of hapten concentrations. Chimera reconstitutions demonstrate that the BM plasma cell defect is B cell intrinsic. Lack of Aiolos does not alter expression of any of the previously described factors required for general plasma cell differentiation. No defect in somatic hypermutation, the generation of memory B cells, or short-lived high affinity plasma cells in the spleen was observed upon rechallenge. These studies support a model by which the high affinity plasma cell population in the BM undergoes a unique differentiation program that is dependent on Aiolos.

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Distinct pathways of plasma cell differentiation and their transcription factor requirements. The differentiation of a responding B cell to either a low affinity short-lived AFC (A) or a GC B cell (B) involves distinct pathways. The GC centroblast (B) undergoes somatic hypermutation of the Ig variable genes. Mutated centrocytes (B′) are selected for proper Ag binding and can further differentiate into a high affinity long-lived BM AFC (C-C′) or into a memory B cell (D) which recirculates throughout the body. Upon antigenic reexposure, the memory B cell rapidly differentiates into either a splenic short-lived AFC of high affinity (E) or a long-lived high affinity BM AFC (F). Aiolos is required for the differentiation of high affinity BM AFCs (C-C′ and F), whereas previously described nuclear factors like XBP-1 or Blimp-1 are required for differentiation of all AFC subsets.
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fig7: Distinct pathways of plasma cell differentiation and their transcription factor requirements. The differentiation of a responding B cell to either a low affinity short-lived AFC (A) or a GC B cell (B) involves distinct pathways. The GC centroblast (B) undergoes somatic hypermutation of the Ig variable genes. Mutated centrocytes (B′) are selected for proper Ag binding and can further differentiate into a high affinity long-lived BM AFC (C-C′) or into a memory B cell (D) which recirculates throughout the body. Upon antigenic reexposure, the memory B cell rapidly differentiates into either a splenic short-lived AFC of high affinity (E) or a long-lived high affinity BM AFC (F). Aiolos is required for the differentiation of high affinity BM AFCs (C-C′ and F), whereas previously described nuclear factors like XBP-1 or Blimp-1 are required for differentiation of all AFC subsets.

Mentions: Upon antigenic stimulation, mature naive B cells accumulate and proliferate in the margins of the splenic T cell zone, known as the periarteriolar lymphoid sheaths, where they enter one of two developmental pathways. In the first of these, naive B cells remain at the margins of the periarteriolar lymphoid sheaths and differentiate into short-lived AFCs (see Fig. 7). These cells are formed early in the response, peak at 8–10 d after immunization, and decline rapidly thereafter (4, 5). They produce low affinity Abs encoded by unmutated rearranged Ig genes. These low affinity extrafollicular AFCs have an immediate effector function that results in the quick clearance of Ag. In the second pathway, Ag-stimulated B cells migrate to the B cell follicle where they form a secondary follicle known as the germinal center (GC; for review see references 6 and 7). The GC is the site for affinity maturation of Ag-specific B cell clones and is characterized by histologically distinct light and dark zones. Within the dark zone of the GC, Ag-specific centroblasts undergo proliferation and somatic hypermutation that randomly diversifies their Ag receptor specificity. The fate of B cell clones that arise within the dark zone of the GC is determined by positive or negative selection in the light zone. A centrocyte will be rescued if it receives two survival signals: the first from follicular dendritic cells containing immune complexes on their complement receptor (CR2), and the second from Ag-specific T cells. It has been proposed that the fate of a centrocyte is determined by the intensity of signals it receives as it reencounters Ag on resident follicular dendritic cells: higher levels of B cell receptor (BCR) signaling select for high affinity variants, intermediate levels send B cells for recycling through the GC the potential benefit of additional mutations, whereas low levels signal death by apoptosis (6). It is from GC B cell clones selected for their high Ag affinity that high affinity AFCs and memory B cells arise.


Aiolos is required for the generation of high affinity bone marrow plasma cells responsible for long-term immunity.

Cortés M, Georgopoulos K - J. Exp. Med. (2004)

Distinct pathways of plasma cell differentiation and their transcription factor requirements. The differentiation of a responding B cell to either a low affinity short-lived AFC (A) or a GC B cell (B) involves distinct pathways. The GC centroblast (B) undergoes somatic hypermutation of the Ig variable genes. Mutated centrocytes (B′) are selected for proper Ag binding and can further differentiate into a high affinity long-lived BM AFC (C-C′) or into a memory B cell (D) which recirculates throughout the body. Upon antigenic reexposure, the memory B cell rapidly differentiates into either a splenic short-lived AFC of high affinity (E) or a long-lived high affinity BM AFC (F). Aiolos is required for the differentiation of high affinity BM AFCs (C-C′ and F), whereas previously described nuclear factors like XBP-1 or Blimp-1 are required for differentiation of all AFC subsets.
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Related In: Results  -  Collection

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fig7: Distinct pathways of plasma cell differentiation and their transcription factor requirements. The differentiation of a responding B cell to either a low affinity short-lived AFC (A) or a GC B cell (B) involves distinct pathways. The GC centroblast (B) undergoes somatic hypermutation of the Ig variable genes. Mutated centrocytes (B′) are selected for proper Ag binding and can further differentiate into a high affinity long-lived BM AFC (C-C′) or into a memory B cell (D) which recirculates throughout the body. Upon antigenic reexposure, the memory B cell rapidly differentiates into either a splenic short-lived AFC of high affinity (E) or a long-lived high affinity BM AFC (F). Aiolos is required for the differentiation of high affinity BM AFCs (C-C′ and F), whereas previously described nuclear factors like XBP-1 or Blimp-1 are required for differentiation of all AFC subsets.
Mentions: Upon antigenic stimulation, mature naive B cells accumulate and proliferate in the margins of the splenic T cell zone, known as the periarteriolar lymphoid sheaths, where they enter one of two developmental pathways. In the first of these, naive B cells remain at the margins of the periarteriolar lymphoid sheaths and differentiate into short-lived AFCs (see Fig. 7). These cells are formed early in the response, peak at 8–10 d after immunization, and decline rapidly thereafter (4, 5). They produce low affinity Abs encoded by unmutated rearranged Ig genes. These low affinity extrafollicular AFCs have an immediate effector function that results in the quick clearance of Ag. In the second pathway, Ag-stimulated B cells migrate to the B cell follicle where they form a secondary follicle known as the germinal center (GC; for review see references 6 and 7). The GC is the site for affinity maturation of Ag-specific B cell clones and is characterized by histologically distinct light and dark zones. Within the dark zone of the GC, Ag-specific centroblasts undergo proliferation and somatic hypermutation that randomly diversifies their Ag receptor specificity. The fate of B cell clones that arise within the dark zone of the GC is determined by positive or negative selection in the light zone. A centrocyte will be rescued if it receives two survival signals: the first from follicular dendritic cells containing immune complexes on their complement receptor (CR2), and the second from Ag-specific T cells. It has been proposed that the fate of a centrocyte is determined by the intensity of signals it receives as it reencounters Ag on resident follicular dendritic cells: higher levels of B cell receptor (BCR) signaling select for high affinity variants, intermediate levels send B cells for recycling through the GC the potential benefit of additional mutations, whereas low levels signal death by apoptosis (6). It is from GC B cell clones selected for their high Ag affinity that high affinity AFCs and memory B cells arise.

Bottom Line: Lack of Aiolos does not alter expression of any of the previously described factors required for general plasma cell differentiation.No defect in somatic hypermutation, the generation of memory B cells, or short-lived high affinity plasma cells in the spleen was observed upon rechallenge.These studies support a model by which the high affinity plasma cell population in the BM undergoes a unique differentiation program that is dependent on Aiolos.

View Article: PubMed Central - PubMed

Affiliation: Cutaneous Biology Research Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA.

ABSTRACT
Antigenic encounter generates long-term immunity sustained by long-lived high affinity plasma cells resident in the bone marrow (BM). Here we show that the Ikaros family member, Aiolos, is specifically required for the generation of these plasma cells. Failure to generate high affinity plasma cells in the BM and to sustain serum antibody titers is apparent after both primary and secondary immunization of Aiolos(-)(/)(-) mice with a range of hapten concentrations. Chimera reconstitutions demonstrate that the BM plasma cell defect is B cell intrinsic. Lack of Aiolos does not alter expression of any of the previously described factors required for general plasma cell differentiation. No defect in somatic hypermutation, the generation of memory B cells, or short-lived high affinity plasma cells in the spleen was observed upon rechallenge. These studies support a model by which the high affinity plasma cell population in the BM undergoes a unique differentiation program that is dependent on Aiolos.

Show MeSH
Related in: MedlinePlus