Induction of the IL-9 gene by HTLV-1 Tax stimulates the spontaneous proliferation of primary adult T-cell leukemia cells by a paracrine mechanism

The etiologic agent of adult T-cell leukemia (ATL) is human T cell lymphotropic virus type 1 (HTLV-1). The HTLV-1 protein Tax alters gene expression, including those of cytokines and their receptors, which plays an important role in early stages of ATL. Here we demonstrate that expression of interleukin-9 (IL-9) is activated by Tax via an NF-kappa B motif in its proximal promoter, whereas IL-9 receptor-a. (IL-9R alpha) expression is not induced by Tax. However, supporting a role for IL-9/IL-9R alpha in ATL, a neutralizing monoclonal antibody directed toward IL-9R alpha inhibited ex vivo spontaneous proliferation of primary ATL cells from several patients. Fluorescence-activated cell sorter analysis of freshly isolated peripheral blood mononuclear cells from these patients revealed high level expression of IL-9Ra on their CD14-expressing monocytes. Furthermore, purified T cells or monocytes alone from these patients did not proliferate ex vivo, whereas mixtures of these cell types manifested significant proliferation through a contact-dependent manner. Taken together, our data suggest that primary ATL cells, via IL-9, support the action of IL-9R alpha/CD14-expressing monocytes, which subsequently support the ex vivo spontaneous proliferation of malignant T cells. In summary, these data support a role for IL-9 and its receptor in ATL by a paracrine mechanism.