Suppression of IL-2-Induced T Cell Proliferation and Phosphorylation of STAT3 and STAT5 by Tumor-Derived TGFβ Is Reversed by IL-15

Abstract

IL-2 responses are susceptible to suppression by TGFβ, 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 TGFβ and subsequent suppression of immune responses. Using TGFβ-producing multiple myeloma tumor cells we demonstrate that tumor-derived TGFβ 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 rTGFβ1. 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 rTGFβ1, 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 TGFβ1-producing tumor cells and rTGFβ1. This finding may be exploited in the design of new immunotherapy approaches that will rely on T cells avoiding tumor-induced suppression.

Uncoupling of Promitogenic and Antiapoptotic Functions of IL-2 by Smad-Dependent TGF-β Signaling

“…Therefore, our results are inconsistent with an inhibitory effect of TGF-␤ at the level of JAKs, or proximal components of the Shc or STAT5 pathways. Furthermore, we failed to see any differential sensitivity to TGF-␤ when comparing IL-2-and IL-15-induced T cell proliferation, in contrast to one of these prior studies (57). The discrepancy between our results and prior studies may reflect the use of different T cell types, stimulation conditions, or other experimental variables.…”

“…It has been reported that TGF-␤ fails to inhibit T cell proliferation in response to IL-15, a cytokine that is closely related to IL-2 (57). This seems at odds with the fact that the IL-15R uses the same ␤ and ␥ c subunits as the IL-2R and appears to activate the same downstream signaling pathways (1).…”

“…1A). Thus, the previously reported differential effect of TGF-␤ on IL-2-vs IL-15-induced proliferation (57) is not applicable in all circumstances and hence does not reflect an invariant property of these receptor systems.…”

“…In an early study, TGF-␤ was reported to inhibit IL-2R-mediated tyrosine phosphorylation of multiple substrates of unknown identity (54). More recently, several groups have reported that TGF-␤, through an unknown mechanism, inhibits the phosphorylation and activation of one or more components of the JAK/STAT pathway, including JAK1, JAK3, STAT5, and STAT3 (55)(56)(57). Based on this, it has been proposed that TGF-␤ antagonizes IL-2R signaling by direct inhibition of proximal signaling events.…”

Laboratory Characterizations on 2007 Cases of Monoclonal Gammopathies in East China

“…In order to investigate the laboratory diagnostic characters of monoclonal gammopathies in large scale in China as well as to analyze the putative genetic predisposing factors, here in this study, we studied the immunological features of 2,007 cases of monoclonal gammopathies from 10,682 suspected samples for laboratory diagnostic confirmation or exclusion with serum protein electrophoresis (SPE), immunofixation electrophoresis (IFE), immunoglobulin (Ig) quantitation (rate nephelometry) as well as urine free light chain ELISA. TGFβ1, the important immune inhibitory cytokine (16), was probed for its association of expression, SNPs with monoclonal gammopathies.…”