title: Suppression of IL-2-induced T cell proliferation and phosphorylation of STAT3 and STAT5 by tumor-derived TGF beta is reversed by IL-15.
abstract: IL-2 responses are susceptible to suppression by TGFbeta, 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 TGFbeta and subsequent suppression of immune responses. Using TGFbeta-producing multiple myeloma tumor cells we demonstrate that tumor-derived TGFbeta 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 rTGFbeta1. 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 rTGFbeta1, 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 TGFbeta1-producing tumor cells and rTGFbeta1. This finding may be exploited in the design of new immunotherapy approaches that will rely on T cells avoiding tumor-induced suppression.
authors: Academic Transfusion Medicine Unit, and Centre for Rheumatic Disease, Department of Medicine, University of Glasgow, Royal Infirmary, Glasgow, United Kingdom. jdmc1v@clinmed.gla.ac.uk
authors: J D
authors: JD
authors: Campbell
authors: G
authors: G
authors: Cook
authors: S E
authors: SE
authors: Robertson
authors: A
authors: A
authors: Fraser
authors: K S
authors: KS
authors: Boyd
authors: J A
authors: JA
authors: Gracie
authors: I M
authors: IM
authors: Franklin
mesh_terms: D002478:Cells, Cultured; D018920:Coculture Techniques; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D007166:Immunosuppressive Agents / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D019409:Interleukin-15 / Q000096:biosynthesis / Q000502:physiology*; D007376:Interleukin-2 / Q000037:antagonists & inhibitors* / Q000502:physiology; D008213:Lymphocyte Activation / Q000276:immunology*; D008262:Macrophage Activation; D008894:Milk Proteins; D009000:Monocytes / Q000276:immunology / Q000378:metabolism; D009101:Multiple Myeloma / Q000276:immunology / Q000473:pathology; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D010766:Phosphorylation; D015375:Receptors, Interleukin-2 / Q000096:biosynthesis; D050796:STAT3 Transcription Factor; D050799:STAT5 Transcription Factor; D015398:Signal Transduction / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D015534:Trans-Activators / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000502:physiology*; D014407:Tumor Cells, Cultured
chemical_list: D004268:DNA-Binding Proteins; D007166:Immunosuppressive Agents; D019409:Interleukin-15; D007376:Interleukin-2; D008894:Milk Proteins; D009363:Neoplasm Proteins; D015375:Receptors, Interleukin-2; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D050799:STAT5 Transcription Factor; D015534:Trans-Activators; D016212:Transforming Growth Factor beta