Anergic T cells are metabolically anergic.
Full T cell activation requires TCR engagement (signal 1) in the context of costimulation (signal 2). Costimulation is required for maximal expression of effector cytokines and prevention of T cell anergy. It has become increasingly clear that another major function of costimulation is to up-regulate the metabolic machinery necessary for T cell function. In this report we demonstrate that anergic T cells are metabolically anergic, in that upon full stimulation (signals 1 plus 2) they fail to up-regulate the machinery necessary to support increased metabolism. These findings suggest that one mechanism responsible for the maintenance of T cell anergy is failure to up-regulate the metabolic machinery. Furthermore, we demonstrate that by blocking leucine, glucose, and energy metabolism, T cell activation is mitigated. Additionally, inhibition of these metabolic pathways during T cell activation leads to anergy in Th1-differentiated cells. Overall, our findings extend the role of T cell metabolism in regulating T cell function.
Zheng
Yan
Y
The Sidney-Kimmel Cancer Research Center, The Johns Hopkins School of Medicine, Baltimore, MD 21231, USA.
Delgoffe
Greg M
GM
Meyer
Christian F
CF
Chan
Waipan
W
Powell
Jonathan D
JD
D055372:AMP-Activated Protein Kinases / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D018106:CD28 Antigens / Q000276:immunology; D017252:CD3 Complex / Q000276:immunology; D002460:Cell Line; D017635:Clonal Anergy; D045304:Cytochromes c / Q000276:immunology; D004734:Energy Metabolism / Q000187:drug effects* / Q000276:immunology; D005947:Glucose / Q000276:immunology / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007155:Immunologic Factors / Q000494:pharmacology; D007930:Leucine / Q000031:analogs & derivatives / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology*; D053858:Metabolic Networks and Pathways / Q000187:drug effects / Q000276:immunology; D051379:Mice; D011948:Receptors, Antigen, T-Cell / Q000276:immunology* / Q000378:metabolism; D012265:Ribonucleotides / Q000494:pharmacology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects / Q000276:immunology
D000911:Antibodies, Monoclonal; D018106:CD28 Antigens; D017252:CD3 Complex; D007004:Hypoglycemic Agents; D007155:Immunologic Factors; D011948:Receptors, Antigen, T-Cell; D012265:Ribonucleotides; D000620:Aminoimidazole Carboxamide; D045304:Cytochromes c; D055372:AMP-Activated Protein Kinases; C031143:AICA ribonucleotide; D007930:Leucine; D005947:Glucose