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The role of cytoplasmic intermediates in IL 2-induced T cell growth
Abstract:
In previous studies we showed that PHA-stimulated human peripheral blood lymphocytes contain an extractable cytoplasmic protein that is capable of inducing DNA synthesis in isolated quiescent nuclei. This factor, which we have called ADR (for activator of DNA replication), appears to represent an endogenous intracellular mitogen, or cytoplasmic transducer of extracellular mitogenic signals. In light of the known role of IL 2 in PHA-induced T cell mitogenesis, we continued these studies to investigate whether ADR may be involved in the mechanism of action of IL 2. Results from both dose-response and time-response studies strongly suggest a functional role for ADR in IL 2 mediated T cell growth. Furthermore, the absence of ADR in dexamethasone-treated, PHA-stimulated cells suggests that the induction of ADR is not an early event in T cell activation associated with the expression of IL 2 receptors; rather, the induction of ADR appears to be a later event resulting directly or indirectly from the binding of IL 2 to IL 2-responsive cells. In sum, our findings suggest a pathway for T cell growth in which extracellular exogenous mitogenic signals are transmitted to the nucleus first through an extracellular endogenous growth factor (IL 2) and finally through an intracellular, endogenous molecule (ADR) that acts at the level of the nucleus itself.
Insights
Activator of DNA replication (ADR) is an intracellular protein that drives DNA synthesis in T cells. This study shows ADR is a key mediator in Interleukin-2 (IL-2) driven T cell growth.
Area of Science:
- Immunology
- Cell Biology
- Molecular Biology
Background:
- Human peripheral blood lymphocytes stimulated with PHA contain a cytoplasmic protein, Activator of DNA replication (ADR).
- ADR induces DNA synthesis in isolated quiescent nuclei, acting as an intracellular mitogen or transducer of extracellular signals.
- Interleukin-2 (IL-2) plays a known role in PHA-induced T cell mitogenesis.
Purpose of the Study:
- To investigate the potential role of ADR in the mechanism of action of IL-2.
- To elucidate the pathway of T cell growth mediated by IL-2 and ADR.
Main Methods:
- Dose-response and time-response studies were conducted.
- PHA-stimulated lymphocytes were analyzed for ADR presence.
- Dexamethasone treatment was used to assess ADR induction timing.
Main Results:
- Dose-response and time-response data strongly suggest ADR has a functional role in IL-2 mediated T cell growth.
- ADR was absent in dexamethasone-treated, PHA-stimulated cells, indicating its induction is a later event in T cell activation.
- ADR induction appears to be a downstream effect of IL-2 binding to responsive cells.
Conclusions:
- Findings suggest a T cell growth pathway involving IL-2 as an extracellular signal and ADR as an intracellular nuclear-acting molecule.
- ADR acts as a crucial intracellular transducer, linking extracellular IL-2 signals to nuclear DNA replication.
- This pathway highlights the sequential transmission of mitogenic signals from extracellular factors to intracellular nuclear events.