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

Abstract

α4 potentially mediates BCR signals through a rapamycin-sensitive TOR pathway. To investigate a potential role for α4 in B cell activation, the α4 gene was disrupted conditionally in B cells by mating male CD19-Cre mice with female α4-floxed mice. CD19-Cre+/α4flox mice showed loss of α4 protein in B lineage cells and a decreased number of phenotypically normal mature B cells. Compared to normal B cells, α4⁻ 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+/α4flox 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 α4 plays a pivotal role in antigen-specific signal transduction during B cell activation and differentiation in vivo.