Recent evidence indicates that cells become malignant when the normal control mechanisms over cell division and proliferation malfunction. The purpose of the studies described in this proposal will be to obtain a better understanding of the mechanisms used by IL-2 and its receptor to promote T-cell proliferation and to define possible sites at which this process may malfunction in malignancy. Normal T-cell growth and clonal proliferation probably occur by an autocrine pathway in which the cell both makes and responds to its own growth factor. Normally induction of IL-2 and its receptor is controlled by the presence of antigen; thus T-cell growth is limited to a subpopulation of antigen-specific cells. However, the autocrine nature of this process suggests that it requires delicate regulation, and we hypothesize that perturbations of the control mechanisms over IL-2 or its receptor may produce a transformed cell. To test this hypothesis we plan to introduce the gene for IL-2 into the IL-2 dependent cell lines CT-6 and CTLL, which constitutively make the IL-2 receptor but not IL-2. If these cells become IL-2 independent, as our preliminary studies indicate, we will test for a transformed phenotype by injecting the cells into mice of a genetic background which is identical to that of the cell line. If tumors cannot be established or if the cells cannot be made to become IL-2 independent, we will change the regulatory regions of the gene to bring it under constitutive control, and determine if the modified gene is capable of conferring the malignant phenotype. In addition we plan to investigate the generality of the growth-promoting properties of the IL-2 receptor by introducing the IL-2 receptor gene into a variety of non-T lymphocytes and other cells and testing for the ability of IL-2 to promote proliferation of the cells receiving the gene. Finally, we will examine the role of the IL-2 receptor in the proliferation of human T-cell lymphomas which express the IL-2 receptor constitutively. We will test the effect of a plasmid producing an anti-sense copy of the IL-2 receptor mRNA on the growth of a HTLV infected cell line which constitutively makes the IL-2 receptor. We will also examine the function of this isolated receptor gene. We anticipate that these studies will help determine if IL-2 or the IL-2 receptor have a role in the pathogenesis of human T-cell malignancies.
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