title: Infectious tolerance via the consumption of essential amino acids and mTOR signaling.
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.
authors: Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, United Kingdom. stephen.cobbold@path.ox.ac.uk
authors: Stephen P
authors: SP
authors: Cobbold
authors: Elizabeth
authors: E
authors: Adams
authors: Claire A
authors: CA
authors: Farquhar
authors: Kathleen F
authors: KF
authors: Nolan
authors: Duncan
authors: D
authors: Howie
authors: Kathy O
authors: KO
authors: Lui
authors: Paul J
authors: PJ
authors: Fairchild
authors: Andrew L
authors: AL
authors: Mellor
authors: David
authors: D
authors: Ron
authors: Herman
authors: H
authors: Waldmann
mesh_terms: D019264:Adoptive Transfer; D000601:Amino Acids, Essential / Q000172:deficiency / Q000378:metabolism*; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003713:Dendritic Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D000939:Epitopes / Q000276:immunology; D051858:Forkhead Transcription Factors / Q000378:metabolism; D007108:Immune Tolerance / Q000187:drug effects / Q000276:immunology*; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011494:Protein Kinases / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology*; D020123:Sirolimus / Q000494:pharmacology; D016038:Skin Transplantation / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000201:enzymology / Q000276:immunology; D058570:TOR Serine-Threonine Kinases; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D000601:Amino Acids, Essential; D000939:Epitopes; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D000081082:Phosphoinositide-3 Kinase Inhibitors; D016212:Transforming Growth Factor beta; D011494:Protein Kinases; C546843:mTOR protein, mouse; C070634:Eif2ak4 protein, mouse; D017346:Protein Serine-Threonine Kinases; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus