High sensitivity of CD4+CD25+ regulatory T cells to extracellular metabolites nicotinamide adenine dinucleotide and ATP: a role for P2X7 receptors.
Although regulatory lymphocytes play an important role in the immune system, the regulation of their functions is poorly understood and remains to be elucidated. In this study we demonstrate that micromolar concentrations of the common cell metabolite NAD induce death in murine forkhead/winged helix transcription factor gene-expressing CD4+CD25+ regulatory T cells with high efficiency and within minutes. Similar, but less dramatic, effects are demonstrable with ATP and its nonhydrolysable derivative, benzoylbenzoyl-ATP. Other T cell subsets are more resistant, with CD8 cells being the least sensitive and CD4 cells expressing intermediate sensitivity. The higher sensitivity of CD4+CD25+ cells is demonstrable in vivo. Injection of NAD or benzoylbenzoyl-ATP causes preferential induction of a cell death signal in CD4+CD25+ cells. Transmission of the death signal requires functional P2X7 receptors, pointing to a role for these receptors in regulation and homeostasis of CD4+CD25+ regulatory T cells. Consistent with this, P2X7R gene-deleted mice possess increased levels of forkhead/winged helix transcription factor gene-expressing CD4+CD25+ cells.
Aswad
Fred
F
Department of Molecular Microbiology and Immunology University of Southern California/Norris Comprehensive Cancer Center, University of Southern California Keck School of Medicine, Los Angeles, CA 90033-0800, USA.
Kawamura
Hiroki
H
Dennert
Gunther
G
D036002:ADP Ribose Transferases / Q000032:analysis; D000255:Adenosine Triphosphate / Q000031:analogs & derivatives / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000032:analysis; D005260:Female; D051858:Forkhead Transcription Factors; D051379:Mice; D008810:Mice, Inbred C57BL; D009243:NAD / Q000494:pharmacology*; D015375:Receptors, Interleukin-2 / Q000032:analysis* / Q000502:physiology; D018048:Receptors, Purinergic P2 / Q000502:physiology*; D058486:Receptors, Purinergic P2X7; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects* / Q000502:physiology
D004268:DNA-Binding Proteins; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; C546469:P2rx7 protein, mouse; D015375:Receptors, Interleukin-2; D018048:Receptors, Purinergic P2; D058486:Receptors, Purinergic P2X7; D009243:NAD; C033901:3'-O-(4-benzoyl)benzoyladenosine 5'-triphosphate; D000255:Adenosine Triphosphate; D036002:ADP Ribose Transferases