PNAS 2009-07-21

Infectious tolerance via the consumption of essential amino acids and mTOR signaling.

Stephen P Cobbold, Elizabeth Adams, Claire A Farquhar, Kathleen F Nolan, Duncan Howie, Kathy O Lui, Paul J Fairchild, Andrew L Mellor, David Ron, Herman Waldmann

Index: Proc. Natl. Acad. Sci. U. S. A. 106 , 12055-60, (2009)

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Abstract

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.