Transformation of human umbilical cord blood T cells by human T-cell leukemia/lymphoma virus.

Abstract

Several isolates of human T-cell leukemia/lymphoma virus (HTLV) were transmitted to normal human T cells obtained from the umbilical cord blood of newborns. T cells from seven specimens were immortalized by infection with different HTLV isolates and their properties were compared with those of' activated uninfected normal T cells grown in the presence of Tcell growth factor (TCGF) and with those of HTLV-positive neoplastic T-cell lines derived from patients with T-cell malignancies. The HTLV-infected cells generally belonged to a class of mature T cells (OKT4' and Leu 3A+) and differed from the normal uninfected cells in that they could be propagated in culture indefinitely; possessed altered morphology, including convoluted nuclei and some bi-and multinucleated giant cells; formed large clumps in culture; demonstrated' a diminished requirement for TCGF; had an increased density of TCGF receptors; often became completely independent of exogenous TCGF; and expressed HLA-DR determinants. These properties of the HTLV-infected cord blood T cells contrasted to those of uncultured cord blood T cells and of cord blood cells stimulated with mitogen-and grown with TCGF but resembled the characteristics of T-cell lines established previously from patients with HTLV-associated T-cell malignancies. This in vitro system offers a-unique opportunity to study the basic mechanism involved in abnormal growth and neoplastic transformation of a specific class of human T cells.The discovery of T-cell growth factor (TCGF) in 1976 (1) enabled the development of the-technology to grow normal and neoplastic mature T cells in vitro for considerable periods of time (2). Using purified TCGF (3), it was possible to grow in culture T cells that exhibited several characteristics of the primary tumor cells from patients with mature T-cell malignancies (2). A type C retrovirus designated human T-cell leukemia/ lymphoma virus (HTLV) was isolated from,some neoplastic Tcell lines (4-7). Detailed characterization of these isolates showed that HTLV is an exogenous human retrovirus closely linked to a subtype of mature T-cell malignancy and distinct from all-known animal retroviruses (8-15). In our laboratory 15 HTLV isolates have been obtained from people of different parts of the world (4-7). In addition, human retrovirus isolates have been inde-., pendently reported by workers in other laboratories (16)(17)(18) and comparative studies have shown that the new isolates are members of the HTLV group (19).HTLV infection of normal T cells can induce long-term growth of the infected cells (16,20). One source of HTLV, the MT-2 cell line, was derived from umbilical cord blood T cells designed to -be a "feeder cell" for growing leukemia T cells in a cocultivation experiment, but the cord blood T cells incidentally became immortalized by an apparent infection with HTLV derived from the leukemia cells (16). Yamamoto et al. (21) recently confirmed this observation by using a MT-2 isolate for infection of human lymphocytes. We have transmitted numerou...

Limiting amounts of p27Kip1 correlates with constitutive activation of cyclin E-CDK2 complex in HTLV-I-transformed T-cells

“…HTLV-I infection disrupts the physiological mechanisms of T-cell growth regulation (Markham et al, 1983;Miyoshi et al, 1981;Popovic et al, 1983;Franchini, 1995). While in the early phase of transformation HTLV-I-infected T-cells require IL-2 to proliferate, in the late phase of HTLV-I transformation, T-cells appear to lose the R point control as indicated by their continuous proliferative state even in the absence of IL-2.…”

The Human T-Cell Leukemia Virus Family, Adult T Cell Leukemia, and AIDS

“…Transmission is achieved easily by co-cultivation with killed virus-producing cells, but only with difficulty when cell-free virus is used. The infected cells take on many of the properties of transformed A TLL cells, including altered morphology, increased growth rate, the tendency to grow in clumps, reduced dependence on TCGF, expression of high levels of the TCGP receptor and HLA-Dr antigens on the cell surface, and (usually) immortalization in culture [22,23,31,32]. In vitro transformation by HTLV-I seems to be much more rapid and efficient than leukemogenesis in vitro.…”

“…Subsequently, transformation was achieved using target T cells shown to be HTLV-I negative [31,32]. HTLV-I is tropic for T cells of the OKT4+ phenotype both in vivo [9] and in vitro [19,31,32].…”

Monographs on the Evaluation of Carcinogenic Risks to Humans

“…HTLV-I infects CD4+ T-cells and occasionally CD8+ T-cells in vitro (Markham et aL., 1983;Popovic et aL., 1983) and, less efficiently, other cells inc1uding macrophages, Bcells and glial cells (Longo et aL., 1984;Hoffman et al, 1992;Koralnik et aL., I992a). ln vivo, HTL V -1 is mainly, if not exc1usively, associated with CD4+ T-cells (Richardson et aL., 1990).…”