title: Mutually exclusive regulation of T cell survival by IL-7R and antigen receptor-induced signals.
abstract: Two major processes govern T cell proliferation and survival: interleukin-7-mediated homeostasis and antigen-induced selection. How cells transit between the two states is unknown. Here we show that T cell receptor ligation actively inhibits homeostatic survival signals while initiating a new, dominant survival programme. This switch is mediated by a change in the expression of pro- and anti-apoptosis proteins through the downregulation of Bcl-2 and the induction of Bim, A1 and Bcl-xL. Calcineurin inhibitors prevent the initiation of the new survival programme, while permitting the dominant repression of Bcl-2. Thus, in the presence of these drugs the response to antigen receptor ligation is cell death. Our results identify a molecular switch that can serve as an attractive target for inducing antigen-specific tolerance in treating autoimmune disease patients and transplant recipients.
authors.affiliation: The Walter and Eliza Hall Institute for Medical Research, Parkville, Victoria 3052, Australia.
authors.forename: Paul
authors.initials: P
authors.lastname: Koenen
authors.forename: Susanne
authors.initials: S
authors.lastname: Heinzel
authors.forename: Emma M
authors.initials: EM
authors.lastname: Carrington
authors.forename: Lina
authors.initials: L
authors.lastname: Happo
authors.forename: Warren S
authors.initials: WS
authors.lastname: Alexander
authors.forename: Jian-Guo
authors.initials: JG
authors.lastname: Zhang
authors.forename: Marco J
authors.initials: MJ
authors.lastname: Herold
authors.forename: Clare L
authors.initials: CL
authors.lastname: Scott
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Lew
authors.forename: Andreas
authors.initials: A
authors.lastname: Strasser
authors.forename: Philip D
authors.initials: PD
authors.lastname: Hodgkin
mesh_terms: D000818:Animals; D002470:Cell Survival; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D011948:Receptors, Antigen, T-Cell / Q000502:physiology*; D020395:Receptors, Interleukin-7 / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D013601:T-Lymphocytes / Q000166:cytology*
chemical_list: D011948:Receptors, Antigen, T-Cell; D020395:Receptors, Interleukin-7