activation, differentiation and immune response

Mammalian TOR is a key component of a signaling pathway that integrates inputs from nutrients and growth factors to regulate cell growth andmetabolism. Because disruption of the mouse mTOR gene leads to early postimplantation lethality, we generated a mouse knockdown model, which recapitulates mTOR inhibition by drugs. Neo insertion interrupts transcription, leading to a 70 % reduction in mTOR expression. The homozygous knockdown mice exhibit reductions in body, organ and cell size. Spleens are disproportionately smaller relative to overall body weight than other organs. Cell proliferation was decreased in splenic B cells. LPS-induced proliferation in B cells was reduced. Splenic B cell populations had more mature cells (IgDhi CD21+ IgM-), with fewer transitional cells (IgDhiIgMhi), and markedly reduced marginal zone B cells (IgDlowCD21hiIgMhi). Phosphorylation of AKT was increased in B cells after LPS stimulation, similar to what has been reported in PBMCs receiving long-term rapamycin treatment. B220+ B cells were decreased in bone marrow and alterations were seen in pre-B cell maturation. Antibody production, germinal center formation and class switch recombination were compromised in the mTOR knockdown mice. These data suggest that mTOR plays a role in the maturation and differentiation of B cell lineages, as well as in the regulation of immune responses