CONSTITUTIVE ACTIVATION OF THE INTERLEUKIN-2 GENE IN THE INDUCTION OFSPONTANEOUS IN-VITRO TRANSFORMATION AND TUMORIGENICITY OF T-CELLS

There is growing evidence to suggest that tumorigenic transformation o f cells may result from aberrant regulation of autocrine growth factor production. In the current study we describe the spontaneous in vitro transformation of T-lymphocyte cell lines during routine cell culture as evidenced by autonomous growth without any requirement for stimula tion or exogenous interleukin 2 (IL-2). These cells constitutively exp ressed the IL-2 gene and were inhibited from proliferating by addition of antibodies against IL-2, the IL-2 receptor, or IL-2 antisense olig onucleotides, thereby suggesting that the cell transformation resulted from IL-2-mediated autocrine growth. The transformed cells when injec ted into nude but not normal mice induced tumors that were inhibited b y antibodies against IL-2 and the IL-2 receptor as well as by inmunosu ppressive drugs such as cyclosporin A. These studies demonstrate that aberrant regulation of IL-2 production can lead to spontaneous transfo rmation of T cells in vitro, capable of inducing tumors in vivo. Our s tudies not only provide evidence for the important role played by auto crine growth factors in tumorigenicity but also stress the need to use caution while performing immunotherapy using in vitro-cultured T cell s against cancer and viral infections, particularly in an immunodefici ent host, to exclude any possible transfer of transformed mutant cells .