Tolerant Metabolism

Science Signaling  11 Jan 2011:
Vol. 4, Issue 155, pp. ec11
DOI: 10.1126/scisignal.4155ec11

Regulatory T cells (Tregs) suppress immune responses and prevent autoimmunity. Whereas the stimulation of effector T cells in vitro leads to their proliferation, Tregs do not proliferate, remaining in an unresponsive (anergic) state; however, stimulation of Tregs in vivo causes their proliferation. To investigate this discrepancy, Procaccini et al. examined the activity in Tregs of the mammalian target of rapamycin (mTOR), a cellular sensor of nutrient status with roles in proliferation. The activity of mTOR was greater in freshly isolated human Tregs than in effector T cells. Acute, but not chronic, exposure to the mTOR inhibitor rapamycin before stimulation of Tregs led to their increased proliferation relative to that of control cells, indicating that mTOR activity was required to maintain the anergic state of Tregs. In a mouse model of autoimmune disease, transient, but not chronic, inhibition of mTOR enhanced the proliferation of Tregs and had beneficial effects on disease outcome. Transient inhibition of mTOR activity in Tregs increased the extent of TCR signaling relative to that of control cells. Analyses of Treg proliferation at various times after stimulation showed that mTOR signaling was increased at later time points compared with that at earlier time points. Thus, whereas early activity of mTOR inhibited Treg proliferation, mTOR was required to maintain proliferation at later time points, which the authors suggest is because of an increased requirement for nutrients. The protein hormone leptin inhibited rapamycin-induced proliferation of Tregs; under normal conditions, Tregs secreted leptin, which activated mTOR in an autocrine manner to maintain anergy. Tregs deficient in the leptin receptor exhibited decreased mTOR activity and increased proliferation compared with that of wild-type cells. Together, these data suggest that the leptin-mTOR axis sets the threshold for the responsiveness of Tregs, which may affect the balance between tolerance and autoimmunity.

C. Procaccini, V. De Rosa, M. Galgani, L. Abanni, G. Cali, A. Porcellini, F. Carbone, S. Fontana, T. L. Horvath, A. La Cava, G. Matarese, An oscillatory switch in mTOR kinase activity sets regulatory T cell responsiveness. Immunity 33, 929–941 (2010). [PubMed]