A central role for the mammalian target of rapamycin in determining the consequences of TCR engagement

The ultimate outcome of an immune response is not dictated by antigen itself but by the context in which the antigen is encountered. In this study, we demonstrate that in T cells the mammalian target of rapamycin (mTOR) senses and integrates environmental cues and plays a central role in the determination of the outcome of TCR engagement.; T cells stimulated with anti-CD3+anti-CD28 in the presence of rapamycin, a potent inhibitor of mTOR, are rendered anergic. However, T cells overexpressing an mTOR that has a mutation in the rapamycin binding site resist to rapamycin-induced anergy. That is, mTOR is necessary for T cell activation, and TCR engagement in the absence of mTOR activity leads to anergy. Furthermore, metabolic inhibition of mTOR by energy deficiency also results in anergy. In vivo, blocking mTOR activity converts a normally activating stimulation into a tolerogenic one. Using TfR as a marker of mTOR activation, we are able to distinguish between activated and anergic T cells. Thus, not only is mTOR activity required for an efficient T cell response, it also can be used to distinguish activated from anergic T cells. mTOR has multiple downstream targets including PP2A, whose activity is inhibited by mTOR activation. Indeed, TCR engagement alone leads to the upregulation of PP2A activity. Furthermore calyculin A, a PP2A inhibitor is able to block anergy induction. More interestingly, TCR engagement in the presence of calyculin A and rapamycin does not result in anergy, suggesting that PP2A is indeed downstream of mTOR and plays an opposing role in the regulation of T cell activation.; Leucine is the most potent amino acid to activate mTOR. T cell activation concomitant with leucine depletion results in anergy. Intriguingly, branched chain amino acid aminotransferase I (BCAT I) which catalyzes the first reaction in leucine catabolism is upregulated in the conditions inducing anergy and decreases in the conditions promoting activation both in vitro and in vivo. These data point to an important role of branched chain amino acids in regulating T cell function.