BCR signal through alpha 4 is involved in S6 kinase activation and required for B cell maturation including isotype switching and V region somatic hypermutation.
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.
Inui
Seiji
S
Department of Immunology, Kumamoto University School of Medicine, 2-2-1 Honjo, Kumamoto 860-0811, Japan.
Maeda
Kazuhiko
K
Hua
Ding Rong
DR
Yamashita
Takeshi
T
Yamamoto
Hideyuki
H
Miyamoto
Eishichi
E
Aizawa
Shinichi
S
Sakaguchi
Nobuo
N
D000818:Animals; D015703:Antigens, CD / Q000502:physiology*; D018941:Antigens, CD19 / Q000502:physiology; D001402:B-Lymphocytes / Q000502:physiology*; D004789:Enzyme Activation; D005260:Female; D017578:Immunoglobulin Class Switching; D007135:Immunoglobulin Variable Region / Q000235:genetics*; D039441:Integrin alpha4; D008213:Lymphocyte Activation; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D011947:Receptors, Antigen, B-Cell / Q000502:physiology*; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism*; D015398:Signal Transduction; D020123:Sirolimus / Q000494:pharmacology; D027041:Somatic Hypermutation, Immunoglobulin
D015703:Antigens, CD; D018941:Antigens, CD19; D007135:Immunoglobulin Variable Region; D011947:Receptors, Antigen, B-Cell; D039441:Integrin alpha4; D019893:Ribosomal Protein S6 Kinases; D020123:Sirolimus