The Interleukin-2 T-Cell System: A New Cell Growth Model

Abstract

Synchronized interleukin-2 receptor-positive T cells, homogeneous immunoaffinity-purified interleukin-2, and a monoclonal antibody to interleukin-2 receptors were used to show that only three factors are critical for T-cell cycle progression: interleukin-2 concentration, interleukin-2 receptor density, and the duration of the interleukin-2 receptor interaction. Since the proliferative characteristics of T cells are identical to those of both prokaryotic and all other eukaryotic cells, these findings provide a new model that accounts fully for the variables that determine cell cycle progression.

The quantal theory of immunity

“…A semi-log plot of the fluorescence intensity of IL2R expression vs. cell number revealed what is now familiar to all immunologists; there is a log-normal (i.e. a normal distribution when cell number is plotted against the log 10 receptor density or fluorescence intensity from flow cytometry data) distribution of IL2Rs on individual cells comprising the population that spans at least two orders of magnitude [13]. cells within the population distributed about the mean in a log-normal fashion between the two extremes.…”

“…After the addition of IL2, cell aliquots were monitored at frequent intervals by short pulses of radiolabeled thymidine. The results were clear-cut; cells with high numbers of IL2Rs traversed the G 1 phase and entered S-phase more rapidly than cells with fewer IL2Rs [13]. Thus, if a cell has fewer IL2Rs it can still eventually progress through the cell cycle to the S-phase, but it takes longer, as if the cell waits until the "proper" number of IL2Rs has been triggered.…”

“…It was not until Leonard Herzenberg and his co-workers introduced the flow cytometer to immunology [12] that it was possible to study T cell proliferation at the level of the single cell [13]. Using propidium iodide to stain the DNA content of cells quantitatively, it was immediately obvious that there is a tremendous heterogeneity among individual cells of a population, even a cloned T cell population.…”

“…Thus, when an asynchronously proliferating cell population is exposed to different IL2 concentrations spanning 1 pM -100 pM, some cells can respond to very low IL2 concentrations, while others require higher IL2 concentrations. At the EC 50 , half of the cells have begun to replicate their DNA, while half have not, when assayed after 24 h of culture [13].…”

“…Pulse exposure of cells to a receptor-saturating concentration of IL2 for varying time intervals (i.e. 3, 6, 11, and 24 h) revealed that even though IL2/IL2R binding comes to steady-state within 10 min [15], a minimum of 6 h was necessary before any cells progressed to S-phase, and those that did so first had the greatest density of IL2Rs [13].…”