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 (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.
Cobbold
Stephen P
SP
Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, United Kingdom. stephen.cobbold@path.ox.ac.uk
Adams
Elizabeth
E
Farquhar
Claire A
CA
Nolan
Kathleen F
KF
Howie
Duncan
D
Lui
Kathy O
KO
Fairchild
Paul J
PJ
Mellor
Andrew L
AL
Ron
David
D
Waldmann
Herman
H
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
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