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Interleukin‐2‐mediated Survival and Proliferative Signals are Uncoupled in T Lymphocytes that Fail to Divide after Activation 1
Author(s) -
Kreisel Daniel,
Sankaran David,
Wells Andrew D.,
Turka Laurence A.
Publication year - 2002
Publication title -
american journal of transplantation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.89
H-Index - 188
eISSN - 1600-6143
pISSN - 1600-6135
DOI - 10.1034/j.1600-6143.2002.020202.x
Subject(s) - population , microbiology and biotechnology , t cell receptor , biology , immunology , cancer research , interleukin 2 , t cell , cell cycle , medicine , cell , cytokine , immune system , genetics , environmental health
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‐x L . 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.