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Suppression of IL-2-Induced T Cell Proliferation and Phosphorylation of STAT3 and STAT5 by Tumor-Derived TGF Is Reversed by IL-15¹

John D. M. Campbell^2,*, Gordon Cook^*, Susan E. Robertson, Alasdair Fraser^*, Kelly S. Boyd^*, J. Alastair Gracie and Ian M. Franklin^*

^* Academic Transfusion Medicine Unit, and Centre for Rheumatic Disease, Department of Medicine, University of Glasgow, Royal Infirmary, Glasgow, United Kingdom

IL-2 responses are susceptible to suppression by TGF, a cytokine widely implicated in suppression of inflammatory responses and secreted by many different tumor cell types. There have been conflicting reports regarding inhibition of IL-2-induced STAT3 and STAT5 phosphorylation by TGF and subsequent suppression of immune responses. Using TGF-producing multiple myeloma tumor cells we demonstrate that tumor-derived TGF can block IL-2-induced proliferation and STAT3 and STAT5 phosphorylation in T cells. High affinity IL-2R expression was required for the suppression of IL-2 responses as a novel CD25^- T cell line proliferated and phosphorylated STAT3 when cultured with tumor cells or rTGF1. Activating T cells with IL-15, which does not use the high affinity IL-2R, completely restored the ability of T cells to phosphorylate STAT3 and STAT5 when cultured with tumor cells. IL-15-treated T cells proliferated normally when cocultured with tumor cells or rTGF1, whereas IL-2 responses were consistently inhibited. Preincubation with IL-15 also restored the ability of T cells to respond to IL-2 by phosphorylating STAT3 and STAT5, and proliferating normally in the presence of tumor cells. IL-2 pretreatment did not restore T cell function. IL-15 also restored T cell responses by T cells from multiple myeloma patients, and against freshly isolated bone marrow tumor samples. Thus, activation of T cells by IL-15 renders T cells resistant to suppression by TGF1-producing tumor cells and rTGF1. This finding may be exploited in the design of new immunotherapy approaches that will rely on T cells avoiding tumor-induced suppression.

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