Abstract 5310: mTOR knock-down mice exhibit altered T and B cell activation, differentiation and immune response

Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC Mammalian TOR (mTOR) regulates cell growth and survival by integrating nutrient and hormonal signals. Because disruption of the mouse mTOR gene leads to early postimplantation lethality, insights into in vivo function of mTOR have been limited. In this study, we generated a mouse knock-down model, which recapitulates treatment with mTOR inhibitors. Neo insertion interrupts transcription, leading to reduced mTOR expression. The homozygous knock-down mice exhibit reductions in body, organ, and cell size. T cell development in the thymus appears normal, however, T cell receptor (TCR)-induced phosphorylation of AKT was reduced in CD4+ and CD8+ T cells. Spleens are disproportionately small relative to overall body weight. The number of CD4+ and CD8+ T cells is reduced in the spleen. Cell proliferation was decreased in splenic T and B cells. Both TCR-mediated proliferation in T cells and LPS-induced proliferation in B cells were reduced. Splenic T cells show reductions in migration to TECK and SDF, and increased FoxP3 expression. Splenic B cell populations had more mature cells, with fewer transitional cells and markedly reduced marginal zone and follicular B cells. Phosphorylation of AKT was increased in B cells after LPS stimulation, similar to what has been reported in tumor cells exposed to long-term rapamycin treatment. B220+ B cells were decreased in bone marrow and alterations were seen in pre-B cell maturation. We investigated the immunologic consequences of immunization with NP-CGG, and knock-down mice show decreases in NP-specific Ig responses and defects in producing primary germinal center reactions. These data suggest that mTOR plays a role in the maturation and differentiation of immune cell lineages, as well as in the regulation of humoral immunity. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5310.