An expanded role of the tumor suppressor TSC1 in T cell tolerance

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. 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 antigenpresenting 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. Thus, understanding the mechanisms governing T cell anergy should provide therapeutic strategies for combating autoimmune diseases and cancer. An expanded role of the tumor suppressor TSC1 in T cell tolerance