| Despite the remarkable specificity of the T cell receptor for its antigen, it is the context in which that signal is received that dictates the outcome of the immune response. The mammalian target of rapamycin (mTOR) is an evolutionarily conserved serine-threonine kinase that integrates environmental cues in somatic cells through two signaling complexes, mTORC1 and mTORC2. As inhibition of this protein with rapamycin results in the induction of T cell anergy, we sought to determine novel binding partners for raptor, a critical subunit of mTORC1. We identified Hsp90 as a chaperone for raptor, as Hsp90 inhibition resulted in a marked reduction of cellular raptor protein levels. Activating cells in the presence of an Hsp90 inhibitor resulted in the induction of anergy. We then sought to determine the roles of metabolic signaling pathways in the avoidance of anergy. Costimulation was required to fully upregulate the metabolic machinery and mTOR activation necessary for T cell activation. Anergic cells, despite receiving costimulation, behave as if they are stimulated through the TCR alone. In addition, inhibition of metabolic signaling pathways resulted in anergy. Knowing the mTOR was an important molecule in the activation of T cells, we sought to delete mTOR in T cells. T cells that lack mTOR develop normally and are activated appropriately upon stimulation. However, they cannot differentiate into T helper 1 (Th1), Th2, or Th17 cells. Instead, they become Foxp3+ regulatory T cells that potently suppress. We next sought to dissect mTOR signaling by specifically deleting mTORC1 and mTORC2 in T cells. T cells lacking Rheb (a critical subunit of mTORC1) lack mTORC1 activity but retain mTORC2 activity. Like mTOR-deficient T cells they cannot become Th1 or Th17 cells when skewed, but retain their ability to become Th2 cells. Conversely, T cells lacking rictor (an mTORC2 subunit) are capable of becoming Th1 and Th17 cells, but fail to differentiate into Th2 cells when skewed. Our data support a new paradigm in which the default pathway for T cells is to regulatory T cells, and that mTOR signaling is required to selectively divert differentiation into properly programmed effector lineages. |
