REGULATION OF NEOPLASTIC T-LYMPHOCYTE AND HEMATOPOIETIC CELL PROLIFERATION

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Binding of the regulatory peptide, interleukin-2 (IL-2), to its specific receptor is a prerequisite for activated T lymphocytes to grow. Deprivation of IL-2 from T-cells results in all the cells coming to rest in GO. Recombinant, purified IL-2 was used to identify biochemical parameters associated with stimulation of these resting T-cells into cell cycle progression. Calcium levels, measured spectrophotometrically using Quin-2 dye, were markedly increased within one minute. No increase was observed with a non-homologous ligand. Also, it was shown that IL-2 stimulates rapid turnover in the phosphoinositol pathway followed by hydrolysis of phosphoinositides. It has been recently demonstrated that IL-2 binding produces a rapid and transient redistribution of protein kinase C (PK-C) from cytosol to cell membrane. This PK-C activity was correlated with the ability of T-cells to express T-cell receptors on their cell surface. Using radiolabeled IL-2 binding and cytofluorometric assays for anti-Tac, a monoclonal antibody to the IL-2 receptor, IL-2 was shown to stimulate increased IL-2 receptor expression on T-cells within 24 hrs. An increased level of IL-2 receptor became detectible by 4 hrs. Analysis of IL-2 receptor numbers after IL-2 stimulation showed major differences between IL-2 (6-9,000 per cell) and anti-Tac (35-45,000 per cell) binding. Resting, previously activated cells stimulated with phorbol esters have nearly equal numbers of binding sites with both ligands. Scatchard analysis of data reveals that the number of binding sites with high affinity (greater than 10-10M) correlated with IL-2 binding numbers and not with anti-Tac binding. Thus, IL-2 stimulation of T-cell growth results in an increased number of Tac antigen binding sites with lower affinity on the cell surface. Herpes-viruses, such as Herpesvirus saimiri (HVS), and RNA tumor viruses, such as Human T-cell leukemia virus (HTLV), can transform T-cells. Studies on metabolic events and IL-2 receptor regulation have shown major differences of growth control between normal and such transformed T-cells.