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Cited by 19T-cell and B-cell ImmunologyNF-κB Signaling PathwaysImmune Response and Inflammation

BCR signal through α4 is involved in S6 kinase activation and required for B cell maturation including isotype switching and V region somatic hypermutation

Inui, Seiji, Maeda, Kazuhiko, Hua, Ding Rong, Yamashita, Takeshi, Yamamoto, Hideyuki, Miyamoto, Eishichi, Aizawa, Shinichi, Sakaguchi, Nobuo·2002·International Immunology
DOI 10.1093/intimm/14.2.177
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Abstract

alpha 4 potentially mediates BCR signals through a rapamycin-sensitive TOR pathway. To investigate a potential role for alpha 4 in B cell activation, the alpha 4 gene was disrupted conditionally in B cells by mating male CD19-Cre mice with female alpha 4-floxed mice. CD19-Cre+/alpha 4flox mice showed loss of alpha 4 protein in B lineage cells and a decreased number of phenotypically normal mature B cells. Compared to normal B cells, alpha 4(-) B cells showed a decreased proliferation in response to the B cell stimulants (anti-IgM antibody plus IL-4, anti-CD40 mAb and lipopolysaccharide), and a reduced S6 kinase activation and rapamycin sensitivity. While CD19-Cre+/alpha 4flox mice showed impaired antibody responses to both T cell-independent and T cell-dependent (TD) antigens, the TD antigen response was markedly impaired as demonstrated by reduced isotype switching, reduced germinal center formation and reduced V region somatic hypermutation. These results show that alpha 4 plays a pivotal role in antigen-specific signal transduction during B cell activation and differentiation in vivo.

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Crossref · 10.1093/intimm/14.2.177

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  • Upon activation by antigens, LPS, or anti-CD40 antibodies, α4 knockout B-cells proliferated significantly less, showing impaired G1/S transition, reduced p70 S6 kinase activation, and reduced rapamycin sensitivity.

    “Upon activation by antigens, LPS or anti-CD40 antibodies, B-cells significantly proliferated less, showing an impaired G1/S transition, reduced p70 S6 kinase activation and reduced rapamycin sensitivity.”

    From Physiologic functions of PP2A: Lessons from genetically modified mice (2019) · cites this paper as [87]

  • α4 knockout mice showed reduced B-cell responses to immunization with T-cell independent and particularly T-cell-dependent antigens, with significant reductions in IgM and IgG production, isotype switching, V region somatic hypermutation, and germinal center formation.

    “The mice also showed reduced B-cell responses to immunization with T-cell independent, and particularly with T-cell-dependent antigens, as witnessed by a significant reduction in IgM and IgG production, isotype switching, V region somatic hypermutation and germinal center formation.”

    From Physiologic functions of PP2A: Lessons from genetically modified mice (2019) · cites this paper as [87]

  • In bone marrow, normal pro-B cells and reduced pre-B cells were noted, while in spleen the number of mature B220+ B-cells was significantly decreased.

    “In bone marrow, a normal number of pro-B cells and a reduced number of pre-B cells was noted, while in spleen, the number of mature B220 + B-cells was significantly decreased.”

    From Physiologic functions of PP2A: Lessons from genetically modified mice (2019) · cites this paper as [87]

  • B-cell-specific knockout of α4 caused impaired B-cell differentiation and reduced proliferation of activated B-cells.

    “Impaired B-cell differentiation and a reduced proliferation of activated B-cells were phenotypes observed in a B-cell-specific KO mouse of α4 [87].”

    From Physiologic functions of PP2A: Lessons from genetically modified mice (2019) · cites this paper as [87]

  • In mice with B-cell-specific conditional knockout of Igbp1 (CD19-Cre), the spleen shows a B-cell maturation defect.

    “-In spleen, B-cell maturation defect [87]”

    From Physiologic functions of PP2A: Lessons from genetically modified mice (2019) · cites this paper as [87]

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Authors
Inui, S., Maeda, K., Hua, D. R., Yamashita, T., Yamamoto, H., Miyamoto, E., Aizawa, S., & Sakaguchi, N.
Affiliations
Kumamoto University (JP)
Corresponding author
Inui, Seiji
ORCID
Venue
International Immunology
Publisher
Oxford University Press (OUP)
Published
2002-02
Volume
14
Issue
2
Pages
177-187
ISSN
  • 0953-8178 (ISSN-L)
  • 1460-2377
DOI
10.1093/intimm/14.2.177
OpenAlex
W2129737994
Cited by
19
References
67
Citations by year
2022: 1 · 2018: 1 · 2014: 1 · 2013: 1 · 2012: 1
FWCI
0.77
Type
journal article
Language
en
Open access
closed
Locations
  • International Immunology (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
  • Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
Keywords
CD49d, B cell receptor signaling, TOR signaling, B cell maturation, class switch recombination, somatic hypermutation, germinal center formation, B cell activation, antibody response, T-independent antigens, T-dependent antigens, conditional knockout
MeSH terms
Animals, B-Lymphocytes, Enzyme Activation, Female, Immunoglobulin Variable Region, Lymphocyte Activation, Male, Receptors, Antigen, B-Cell, Signal Transduction, Antigens, CD, Immunoglobulin Class Switching, Mice, Knockout, Antigens, CD19, Ribosomal Protein S6 Kinases, Sirolimus, Somatic Hypermutation, Immunoglobulin, Integrin alpha4, Mice

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