Transgenic overexpression of G5PR that is normally augmented in centrocytes impairs the enrichment of high-affinity antigen-specific B cells, increases peritoneal B-1a cells, and induces autoimmunity in aged female mice
Abstract
To investigate signals that control B cell selection, we examined expression of G5PR, a regulatory subunit of the serine/threonine protein phosphatase 2A, which suppresses JNK phosphorylation. G5PR is upregulated in activated B cells, in Ki67-negative centrocytes at germinal centers (GCs), and in purified B220(+)Fas(+)GL7(+) mature GC B cells following Ag immunization. G5PR rescues transformed B cells from BCR-mediated activation-induced cell death by suppression of late-phase JNK activation. In G5PR-transgenic (G5PR(Tg)) mice, G5PR overexpression leads to an augmented generation of GC B cells via an increase in non-Ag-specific B cells and a consequent reduction in the proportion of Ag-specific B cells and high-affinity Ab production after immunization with nitrophenyl-conjugated chicken γ-globulin. G5PR overexpression impaired the affinity-maturation of Ag-specific B cells, presumably by diluting the numbers of high-affinity B cells. However, aged nonimmunized female G5PR(Tg) mice showed an increase in the numbers of peritoneal B-1a cells and the generation of autoantibodies. G5PR overexpression did not affect the proliferation of B-1a and B-2 cells but rescued B-1a cells from activation-induced cell death in vitro. G5PR might play a pivotal role in B cell selection not only for B-2 cells but also for B-1 cells in peripheral lymphoid organs.
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Young G5PR transgenic mice showed no apparent phenotypes in splenic B-cells under non-immunized conditions.
“Young mice showed no apparent phenotypes in splenic B-cells under non-immunized conditions.”
From Physiologic functions of PP2A: Lessons from genetically modified mice (2019) · cites this paper as [80]
Upon immunization with nitrophenyl-conjugated chicken γ-globulin, G5PR transgenic mice had more germinal center B-cells, increased non-antigen-specific B-cells, decreased antigen-specific B-cells, and decreased antibody production.
“upon immunization with nitrophenyl-conjugated chicken γ-globulin, more germinal center B-cells were noted, with an increase in non-antigen-specific B-cells and decreased numbers of antigen-specific B-cells, and decreased antibody production.”
From Physiologic functions of PP2A: Lessons from genetically modified mice (2019) · cites this paper as [80]
Transgenic overexpression of G5PR in lymphoid cells achieved a 4.5-times overexpression in isolated splenocytes.
“in which a 4.5-times overexpression of G5PR was confirmed in isolated splenocytes.”
From Physiologic functions of PP2A: Lessons from genetically modified mice (2019) · cites this paper as [80]
This was associated with severely decreased JNK signaling and suppressed caspase-3 activation.
“This was associated with severely decreased JNK signaling and suppressed caspase-3 activation.”
From Physiologic functions of PP2A: Lessons from genetically modified mice (2019) · cites this paper as [80]
Upon aging, nonimmunized G5PR transgenic mice showed increased peritoneal B-1a cells that were not caused by increased proliferation, but attributed to prevention of BCR-activation-induced apoptosis.
“Upon aging (> 40 weeks), nonimmunized mice showed increased numbers of peritoneal B-1a cells that were not caused by increased proliferation of B-1a or B-2 cells, but attributed to prevention of BCR-activation-induced apoptosis.”
From Physiologic functions of PP2A: Lessons from genetically modified mice (2019) · cites this paper as [80]
In aged female but not male G5PR transgenic mice, these persistent B-1a cells resulted in development of autoimmunity and autoantibody production.
“in aged female but not male transgenic mice, these persistent B-1a cells resulted in development of autoimmunity and autoantibody production [80].”
From Physiologic functions of PP2A: Lessons from genetically modified mice (2019) · cites this paper as [80]
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Physiologic functions of PP2A: Lessons from genetically modified mice
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- Authors
- Kitabatake, M., Toda, T., Kuwahara, K., Igarashi, H., Ohtsuji, M., Tsurui, H., Hirose, S., & Sakaguchi, N.
- Affiliations
- Kumamoto University (JP)
- Juntendo University (JP)
- Corresponding author
- Kitabatake, Masahiro
- Toda, Teppei
- Kuwahara, Kazuhiko
- Igarashi, Hideya
- Sakaguchi, Nobuo
- Venue
- The Journal of Immunology
- Publisher
- Oxford University Press (OUP)
- Published
- 2012-08-01
- Volume
- 189
- Issue
- 3
- Pages
- 1193-1201
- ISSN
- 0022-1767 (ISSN-L)
- 1550-6606
- OpenAlex
- W2162133040
- Cited by
- 12
- References
- 36
- Citations by year
- 2025: 1 · 2024: 2 · 2022: 1 · 2021: 1 · 2020: 1 · 2019: 1 · 2018: 1 · 2016: 1 · 2015: 3
- FWCI
- 0.42
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The Journal of Immunology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Japan Society for the Promotion of Science (23390122, 24590491, 23791116, 22590194, 24659224)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Health Sciences › Medicine › Rheumatology › Systemic Lupus Erythematosus Research
- Health Sciences › Medicine › Pathology and Forensic Medicine › Lymphoma Diagnosis and Treatment
- Keywords
- PP2A regulatory subunit, JNK phosphorylation, B cell selection, centrocytes, germinal center B cells, affinity maturation, B-1a cells, autoimmunity, autoantibodies, activation-induced cell death, transgenic mice, B cell differentiation
- MeSH terms
- Aging, Animals, Autoimmune Diseases, Chickens, Female, Mice, Inbred C57BL, Mice, Inbred NZB, Mice, Transgenic, Nuclear Proteins, Peritoneal Cavity, Phosphoprotein Phosphatases, Rats, Inbred Lew, Sex Characteristics, Up-Regulation, B-Lymphocyte Subsets, Germinal Center, Epitopes, B-Lymphocyte, Protein Subunits, Mice, Rats
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