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

doi:10.1073/pnas.0903919106

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

^aSir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, United Kingdom;
^bImmunotherapy Center, Department of Medicine, Medical College of Georgia, Augusta, GA 30912; and
^cSkirball Institute of Biomolecular Medicine, Department of Medicine, New York School of Medicine, New York, NY 10016

Communicated by Michael Sela, Weizmann Institute of Science, Rehovot, Israel, May 8, 2009 (received for review February 2, 2009)

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-β.

Footnotes

¹To whom correspondence should be addressed. E-mail: stephen.cobbold{at}path.ox.ac.uk
Author contributions: S.P.C., E.A., and H.W. designed research; S.P.C., E.A., C.A.F., K.F.N., D.H., K.O.L., and P.J.F. performed research; A.L.M. and D.R. contributed new reagents/analytic tools; S.P.C. analyzed data; and S.P.C. and H.W. wrote the paper.
Conflict of interest statement: S.P.C. and H.W. are shareholders in TolerRx Inc. and receive royalties for CAMPATH antibody sales. S.P.C. is a shareholder and adviser to BioAnaLab Ltd. A.L.M. has intellectual property interests in the therapeutic use of IDO and IDO inhibitors and receives consulting income from NewLink Genetics Inc.
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