Infectious tolerance via the consumption of essential amino acids and mTOR signaling.
Cobbold SP., Adams E., Farquhar CA., Nolan KF., Howie D., Lui KO., Fairchild PJ., Mellor AL., Ron D., Waldmann H.
Infectious tolerance describes the process of CD4(+) regulatory T cells (Tregs) converting naïve T cells to become additional Tregs. We show that antigen-specific Tregs induce, within skin grafts and dendritic cells, the expression of enzymes that consume at least 5 different essential amino acids (EAAs). T cells fail to proliferate in response to antigen when any 1, or more, of these EAAs are limiting, which is associated with a reduced mammalian target of rapamycin (mTOR) signaling. Inhibition of the mTOR pathway by limiting EAAs, or by specific inhibitors, induces the Treg-specific transcription factor forkhead box P3, which depends on both T cell receptor activation and synergy with TGF-beta.