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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adoptive Transfer
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Amino Acids, Essential / deficiency
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Amino Acids, Essential / metabolism*
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Animals
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Cell Proliferation / drug effects
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Cell Survival / drug effects
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Dendritic Cells / cytology
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Dendritic Cells / drug effects
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Dendritic Cells / immunology
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Epitopes / immunology
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Forkhead Transcription Factors / metabolism
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Immune Tolerance / drug effects
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Immune Tolerance / immunology*
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Lymphocyte Activation / drug effects
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Mice
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Phosphoinositide-3 Kinase Inhibitors
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Protein Kinases / metabolism*
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Protein Serine-Threonine Kinases / metabolism
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Signal Transduction / drug effects
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Signal Transduction / immunology*
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Sirolimus / pharmacology
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Skin Transplantation / immunology
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T-Lymphocytes, Regulatory / cytology
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T-Lymphocytes, Regulatory / enzymology
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T-Lymphocytes, Regulatory / immunology
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TOR Serine-Threonine Kinases
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Transforming Growth Factor beta / metabolism
Substances
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Amino Acids, Essential
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Epitopes
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Forkhead Transcription Factors
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Foxp3 protein, mouse
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Phosphoinositide-3 Kinase Inhibitors
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Transforming Growth Factor beta
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Protein Kinases
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mTOR protein, mouse
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Eif2ak4 protein, mouse
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Protein Serine-Threonine Kinases
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TOR Serine-Threonine Kinases
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Sirolimus