Interleukin 2 inhibits in vitro growth of human T cell lines carrying retrovirus.

Abstract

Human T cell leukemia virus (HTLV), which we previously called adult T cell leukemia virus (ATLV), is a possible causative agent of human adult T cell leukemia (ATL) (1). Since the HTLV genome was demonstrated not to contain a typical v-onc gene (2) and the HTLV proviral genome is integrated into random sites in cellular DNA of leukemia cells in each ATL patient (3), the mechanism of HTLV-induced oncogenesis is still unknown. The interleukin 2 (IL-2) autocrine hypothesis can be excluded as the mechanism of ATL leukemogenesis, because the IL-2 receptor (IL-2R) was detected in all ATL leukemia cells and HTLV-transformed human T cells that were examined (4), but the IL-2 gene was not transcribed in most of these cells (5). However, it was reported (6) that expression of the IL-2R is abnormal in ATL leukemia cells because it is not down-regulated by anti-IL-2R (Tac) antibody, and is constitutive, while IL-2R expression in peripheral blood leukocytes (PBL) stimulated with concanavalin A is down-regulated. This observation resulted in another hypothesis, that the constitutive expression of the IL-2R may play a crucial role in ATL leukemogenesis. Our recent observation (7) that HTLV can induce expression of the IL-2R on human B cell lines, strongly supports the notion that HTLV directly contributes to the constitutive production of the IL-2R on ATL leukemia cells and other HTLV-carrying human T cells. However, it is still unknown how the cell growth signal can be transduced constitutively from the IL-2R expressed on ATL leukemia cells and HTLV-transformed cell lines. Similarly, it has been demonstrated (8) that the A431 human epidermoid carcinoma cell line has a large number of receptors for the epidermal growth factor (EGF) that could be products of the c-erbB gene, a cellular oncogene, and it is suggested (8) that overproduction or uncontrolled expression of the EGF receptors could be related to the appearance of the transformed phenotype in the A431 cell line.We previously (4) obtained HTLV-carrying human T cell lines of two distinct types with respect to their IL-2 dependency. One type (ILT) is IL-2 dependent; the other (TL) is IL-2 independent for in vitro growth. Most of the IL-2-independent TL cell lines arose spontaneously from IL-2-dependent ILT cell lines in vitro. This change from IL-2 dependence to IL-2 independence could be due to immortalizing transformation of the cells induced by HTLV (9, 10).

Characterization of interleukin 2-stimulated phosphorylation of 67 and 63 kDa proteins in human T-cells

“…IL-2-stimulated phosphorylation of pp67 was similarly detected in IL-2-independent HTLV-I-transformed T-cell lines which express the high-and low-affinity receptors for IL-2. In contrast with IL-2-dependent cells, the growth of these cells is inhibited by the addition of IL-2 [39], and we have already proved that the growth-inhibitory signal is transduced from the high-affinity IL-2 receptors by analogy to the IL-2 growth signal [40]. MT-1 cells express only the low-affinity IL-2 receptors constitutively [37] and do not respond to IL-2 with regard to cell-growth promotion and inhibition [39].…”

“…In contrast with IL-2-dependent cells, the growth of these cells is inhibited by the addition of IL-2 [39], and we have already proved that the growth-inhibitory signal is transduced from the high-affinity IL-2 receptors by analogy to the IL-2 growth signal [40]. MT-1 cells express only the low-affinity IL-2 receptors constitutively [37] and do not respond to IL-2 with regard to cell-growth promotion and inhibition [39]. Interestingly the phosphorylation of pp67 (and pp63s) in MT-I was not enhanced by IL-2 at any dose (T. Ishii & K. Sugamura, unpublished work), so it is suggested that the pp67 phosphorylation signal may be transduced from the high-affinity IL-2 receptors.…”

Selective Inhibition of High‐ but Not Low‐Affinity Interleukin 2 Binding by Lectins and Anti‐Interleukin 2 Receptor α Antibody

“…Two classes of IL-2R differing in affinities to IL-2 were identified; these are high-and low-affinity receptors (11,16). The high-affinity receptor, but not the low-affinity receptor, is thought to mediate various functions such as internalization of IL-2 (4, 21), activation of protein kinase C (2), phosphorylation of certain cellular proteins (5,6), and enhancement of gene expression (1,12), and consequently to be involved in cell growth promotion (10) or inhibition in some cases (15) . two different chains, IL-2Rƒ¿ and ƒÀ chains, the IL-2Rƒ¿ chain corresponding to the Tac molecule detected by monoclonal antibody and the IL-2RƒÀ chain identified as 68-72kD glycoproteins (18,20 EffectsofWGA and H-47 Antibody after Additionof 1251-IL-2 We next examined the effects of lectins on IL-2R in the high-affinity state after addition of IL-2.…”

IL‐2‐ and IL‐2‐R‐ independent proliferation of T‐cell lines from adult T‐cell leukemia/lymphoma patients

“…The addition of purified IL-2 preparation did not alter the proliferative state of IL-2-independent ATL cells and cell lines (Tables 111 and IV). More recently, Sugamura et al (1985) observed that exogenous IL-2 added to the culture inhibited proliferation of 4 HTLV-I carrying T-cell lines derived from 3 HTLV-I healthy carriers and an ATL patient. In their discussion they suggested that those IL-2-dependent T-cell lines were possibly derived from activated normal T cells infected with HTLV-I in vivo, based on the observation that ATL leukemia cells can hardly proliferate in the presence of IL-2 during primary culture.…”