During intrathymic T cell development, a huge repertoire of T cells with different antigen specificities are generated through somatic recombination at the T cell receptor (TCR) loci, which equips T cells with the capacity to recognize diverse microbial and environmental antigens. Within such a repertoire of T cells, self-reactive T cells exist and, if not properly controlled, can cause self-inflicted damage to tissues and result in autoimmune diseases. Under normal situations, such self-reactive T cells are kept in check by multiple peripheral tolerance mechanisms, including induction of anergy.Citation1
In the peripheral lymphoid organs, most T cells reside in a naïve resting state. Naïve T cells can be readily activated to become effector T cells that perform an immune function after engagement of the TCR with foreign peptides presented by antigen-presenting cells. T cell activation is accompanied by proliferation, enlargement in size, production of effector molecules (such as cytokines) and high metabolic rate. To induce full T cell activation, the TCR signal alone is not sufficient; concurrent signals from costimulatory molecules, such as CD28 and cytokine receptors, are also required. In the absence of co-stimulation, the TCR signal alone induces T cell anergy rather than full activation. Anergic T cells are hyporesponsive to TCR restimulation, even in the presence of proper costimulation; they are metabolically inert, defective in proliferation and impaired in cytokine production. T cell anergy is important not only for self-tolerance, but also for contributing to tumor immune evasion.Citation1 Thus, understanding the mechanisms governing T cell anergy should provide therapeutic strategies for combating autoimmune diseases and cancer.
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;Citation2-Citation5 in B cell development;Citation6 in mast cell survival and functionCitation7 and in proper innate immune responses and endotoxin shock.Citation8 We have recently found that TSC1 is expressed at higher levels in anergic T cells than in activated T cells.Citation9 In T cells, mTOR is activated following TCR engagement via the PI3K/Akt and the RasGRP1-Ras-Erk1/2 pathways ().Citation10 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.Citation9 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.
The resistance of TSC1KO T cells to anergy is correlated with increased mTORC1 signaling and can be reverted by rapamycin treatment, indicating that TSC1 promotes T cell anergy via inhibiting mTORC1.Citation9 Interestingly, the inducible T cell costimulator (ICOS) expression is increased in TSC1KO T cells, and blocking ICOS signaling partially renders TSC1KO T cells sensitive to anergy, suggesting that TSC1 inhibits ICOS expression to ensure the dependence on CD28 co-stimulation for T cell activation. In addition, the upregulation of anergy-promoting molecules, such as Egr2/3, Itch, Grail and DGKζ, was impaired in TSC1KO T cells following anergizing treatment, raising the possibility that TSC1 may promote T cell anergy via multiple mechanisms. Further investigation of how TSC1/2-mTOR may control the expression of ICOS and anergy-promoting molecules and how TSC1/2 themselves are regulated in T cells should provide additional insight into the mechanism’s control of T cell anergy and tolerance.
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