The tumor suppressor TSC1, in association with TSC2, inhibits the activation of the mammalian target of rapamycin complex 1 (mTORC1) via the GAP activity of the TSC1/2 complex. Several recent studies have revealed the critical role of TSC1 in normal T cell homeostasis, survival and quiescence; 2-5 in B cell development; 6 in mast cell survival and function7 and in proper innate immune responses and endotoxin shock. 8 We have recently found that TSC1 is expressed at higher levels in anergic T cells than in activated T cells. 9 In T cells, mTOR is activated following TCR engagement via the PI3K/Akt and the RasGRP1-Ras-Erk1/2 pathways (Fig. 1). 10 Recent studies have demonstrated that mTOR performs crucial regulatory roles in effector T cell differentiation, inducible regulatory T cell differentiation, T cell trafficking and memory T cell responses to viral pathogens. Given the role of mTOR in T cell activation, we hypothesized that TSC1 may play an important role in T cell anergy by modulating mTOR activity. This hypothesis is proved right by our most recent studies using mice with T cell-specific deletion of TSC1. 9 While WT anergic T cells contain low mTORC1 activity, TSC1-deficient (TSC1KO) T cells pretreated with anergizing condition maintained mTORC1 signaling at a level similar to WT-activated T cells, supporting that TSC1 is critical for decreased mTOR activity in anergic T cells. In vitro, WT naïve CD4 T cells become anergic after TCR simulation and when CTLA4-Ig was added to block CD28-mediated costimulation. These T cells produced much less IL-2 and IFNγ and proliferated less than fully activated T cells after TCR and anti-CD28 restimulation. However, TSC1KO

CD4 T cells that underwent similar anergy-inducing treatment retained the ability to produce these cytokines and proliferated vigorously. In addition, the low metabolic rate typically seen in anergic T cells was not observed in TSC1KO T cells following anergizing treatment. The resistance of TSC1-deficient T cells to anergy was further confirmed in vivo using the Staphylococcus enterotoxin B (SEB) superantigen-induced TCRVβ8+ T cell anergy model. Ultimately, aged and TSC1-deficient mice develop autoimmune diseases in the thyroid gland and liver. The autoimmune diseases in TSC1KO mice appear mild, which could be partly due to the propensity of TSC1 effector T cells to death. Additionally, it is unclear whether regulatory T cell function is altered in absence of TSC1.