Interleukin-2-mediated survival and proliferative signals are uncoupled in T lymphocytes that fail to divide after activation.
T lymphocytes are heterogeneous with respect to their ability to proliferate following activation in vitro and in vivo. Approximately 30% of T lymphocytes fail to progress through the cell cycle, despite showing evidence of an activated state. The population of T lymphocytes that remains undivided during a primary stimulation has been shown to be refractory to restimulation via the TCR and fails to proliferate in response to IL-2. In an in vitro model of T-cell deletion following clonal expansion, we demonstrate that T lymphocytes that do not progress through the cell cycle during primary stimulation have a sevenfold greater survival advantage compared with T lymphocytes that have divided. Progression through multiple division cycles is associated with down-regulation of Bcl-2 during a postactivation period of growth factor withdrawal. However this alone does not account for diminished survival, as constitutive expression of a Bcl-2 transgene did not restore survival to the levels seen in undivided cells. Engagement of the IL-2 receptor on these undivided activated T lymphocytes leads to enhanced survival and up-regulation of Bcl-2 and Bcl-xL. Surprisingly, while IL-2 also induces phosphorylation of Akt, it does not initiate cell cycle progression in this population of primary undivided cells. Our data provide evidence that a T cell's survival capacity is linked to its proliferative behavior. Furthermore, our results provide the first report of a population of T cells, in which the IL-2 receptor-mediated signaling pathways leading to survival and proliferation are naturally uncoupled.
Kreisel
Daniel
D
Department of Medicine, University of Pennsylvania, Philadelphia 19104, USA.
Sankaran
David
D
Wells
Andrew D
AD
Turka
Laurence A
LA
D000818:Animals; D017209:Apoptosis / Q000235:genetics; D002455:Cell Division / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D005434:Flow Cytometry; D007376:Interleukin-2 / Q000494:pharmacology*; D008213:Lymphocyte Activation / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010766:Phosphorylation; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000032:analysis / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects*; D013154:Spleen / Q000276:immunology; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D051020:bcl-X Protein
C494812:Bcl2l1 protein, mouse; D007376:Interleukin-2; D019253:Proto-Oncogene Proteins c-bcl-2; D051020:bcl-X Protein