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Is Reversed by IL-151
*
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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