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

Research output: Contribution to journalArticle

204 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)12055-12060
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume106
Issue number29
DOIs
StatePublished - Jul 21 2009

Keywords

  • Amino acid catabolism
  • Foxp3
  • Rapamycin
  • Regulatory T cells
  • mTOR inhibitor

ASJC Scopus subject areas

  • General

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    Cobbold, S. P., Adams, E., Farquhar, C. A., Nolan, K. F., Howie, D., Lui, K. O., Fairchild, P. J., Mellor, A. L., Ron, D., & Waldmann, H. (2009). Infectious tolerance via the consumption of essential amino acids and mTOR signaling. Proceedings of the National Academy of Sciences of the United States of America, 106(29), 12055-12060. https://doi.org/10.1073/pnas.0903919106