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

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 (EA...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2009-07, Vol.106 (29), p.12055-12060
Main Authors: Cobbold, Stephen P, Adams, Elizabeth, Farquhar, Claire A, Nolan, Kathleen F, Howie, Duncan, Lui, Kathy O, Fairchild, Paul J, Mellor, Andrew L, Ron, David, Waldmann, Herman
Format: Article
Language:English
Subjects:
Adoptive Transfer
Amino acids
Amino Acids, Essential - deficiency
Amino Acids, Essential - metabolism
Animals
Antigens
Biochemistry
Biological Sciences
Cell Proliferation - drug effects
Cell Survival - drug effects
Dendritic cells
Dendritic Cells - cytology
Dendritic Cells - drug effects
Dendritic Cells - immunology
Enzymes
Epitopes - immunology
Exercise tolerance
Forkhead Transcription Factors - metabolism
Immune tolerance
Immune Tolerance - drug effects
Immune Tolerance - immunology
Lymphocyte Activation - drug effects
Mammals
Mast cells
Mice
Phosphoinositide-3 Kinase Inhibitors
Protein Kinases - metabolism
Protein Serine-Threonine Kinases - metabolism
Signal Transduction - drug effects
Signal Transduction - immunology
Sirolimus - pharmacology
Skin grafts
Skin Transplantation - immunology
T cell receptors
T lymphocytes
T-Lymphocytes, Regulatory - cytology
T-Lymphocytes, Regulatory - enzymology
T-Lymphocytes, Regulatory - immunology
TOR Serine-Threonine Kinases
Transforming Growth Factor beta - metabolism
Transplantation tolerance
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Summary: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.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.0903919106