IL-2R Beta Chain Research Articles

Reconstitution of a functional IL-2 receptor by the beta-chain cDNA. A newly acquired receptor transduces negative signal.

The high-affinity IL-2R results from the noncovalent association between at least two subunits; alpha (p55) and beta (p70), both of which are capable of binding IL-2 with a low and intermediate affinity, respectively. Although the alpha-chain itself has been shown to be nonfunctional, suggestions have been made that the beta-chain mediates an IL-2 signal. To directly study the role of the beta-chain in the signal transduction, we transfected with the cDNA encoding the IL-2R beta-chain a human T lymphotropic virus-I-transformed T cell line, MT-1 originally expressing low-affinity alpha-chain alone, and established a stable transformant (designated MT-beta 7) which expressed both alpha- and beta-chains simultaneously. We showed 1) MT-beta 7 manifested the high-affinity IL-2 binding, which was completely disrupted by the anti-beta chain mAb (Mik-beta 1), 2) the 125I-IL-2 crosslinking patterns of MT-beta 7 were indistinguishable from those of cells expressing the native high-affinity IL-2R, 3) MT-beta 7, but not parental MT-1, internalized the bound IL-2 and responded to IL-2 with a negative signal, i.e., inhibition of the de novo DNA synthesis. These results clearly demonstrate that the beta-chain not only participates in forming the high-affinity IL-2R with the alpha-chain but also is directly involved in the IL-2 signal transduction.

Human interleukin 2 (IL 2) receptor beta chain allows transduction of IL 2-induced proliferation signal(s) in a murine cell line.

Interleukin 2 (IL 2) delivers cell growth signal by virtue of its interaction with the high-affinity receptor complex, which consists of two distinct IL 2-binding molecules: the IL 2 receptor alpha (IL 2R alpha) and beta (IL 2R beta) chains. Unlike many known growth factor receptors, neither of the IL 2R chains seems to contain a tyrosine kinase domain. In this report, we have shown that the human IL 2R beta chain expressed in a murine IL 3-dependent, non-lymphoid cell line can transduce IL 2-induced cell proliferation signal(s) in combination with the autologous mouse IL 2R alpha chain. This observation should provide a tool to dissect IL 2-induced signal transduction pathway in lymphoid and non-lymphoid cells.

Transient induction of IL-2 receptor in cultured T cell lines by HTLV-1 LTR-linked tax-1 gene.

Human lymphotropic virus, HTLV-1, encodes in its proviral genome a transcriptional activator protein, tax-1, that may be responsible for the development of virus-induced adult T cell leukemia (ATL), possibly through the aberrant activation of the genes for interleukin-2 (IL-2) and one of its receptor (IL-2R) components, the IL-2 receptor alpha-chain (IL-2R alpha). In the present study, an expression plasmid containing tax-1 cDNA under the control of HTLV-1 LTR was introduced into mouse and human CD4-positive T cell lines. Analysis of the established cell clones revealed a number of interesting features: (i) a limited fraction of the total cell population (less than 25% in each clone) was positive for IL-2R alpha; (ii) the IL-2R alpha expression was not permanent, as the IL-2R alpha positive and negative cells could convert either way. The experimental data suggest that the observed heterogeneity in IL-2R alpha expression in the transformants is due to a cell-cycle-regulated expression and function of tax-1. Furthermore, a proportion of the induced IL-2R in EL-4 was in high-affinity form, suggesting the association of the IL-2R alpha and the IL-2R beta chain (p70-75) components.

Protein phosphorylation mediated by IL-2/IL-2 receptor beta-chain interaction.

We previously found that IL-2 rapidly induced protein phosphorylation of a 67-kDa (pp67) and four 63-kDa (pp63s) cellular proteins in various T cells. Here, we show that the IL-2-stimulated phosphorylation is mediated by the IL-2R beta-chain composed of the high affinity IL-2R, and induced by activation of Ca2+/phospholipid-dependent protein kinase C (PKC). The IL-2-stimulated phosphorylation was always observed in various T cell lines bearing high affinity IL-2R, but never observed in cells which express only low affinity IL-2R consisted of alpha-chain alone. When the expression of high affinity IL-2R was modified by anti-IL-2R mAb for reducing the affinity to 8- to 10-fold lower without affecting the sites of IL-2R, the effective dose of IL-2 on phosphorylation of pp67 increased 8 to 10 times. When cells were treated with pronase, approximately 95% sites of low affinity IL-2R were selectively decreased, but the IL-2 dose dependency for pp67 phosphorylation was little affected. These data exactly suggest that protein phosphorylation in response to IL-2 such as pp67 and pp63s, is mediated by high affinity but not low affinity IL-2R. Furthermore, the IL-2-stimulated phosphorylation of these proteins was also observed in MLA 144 cells which express only low affinity IL-2R consisting of beta-chain alone. In addition, various phorbol esters and tumor promoters, which activate PKC, were also demonstrated to induce the phosphorylation of a pp67 and pp63s in these T cell lines. Therefore, the present study suggests that IL-2/IL-2R beta-chain interaction triggers the phosphorylation of pp67 and pp63s, where the PKC may have an important role.