Autocrine transforming growth factor-beta from chronic lymphocytic leukemia-B cells interferes with proliferative T cell signals

Chronic lymphocytic leukemia (CLL) is characterized by the accumulation of noncycling B cells in lymphatic and extralymphatic tissues. In the present study we investigated the possible contribution of TGF-beta, as secreted by CLL-B cells, on this low proliferative state. CLL-B cells were shown to ex press TGF-beta RNA and to release bioactive TGF-beta into culture supernata nts. Antibody neutralization of endogenously secreted TGF-beta increased th e proliferation of CLL-B cells as cultured in the presence of IL-2 or IL-4 or in direct contact with activated CD4(+) T cells. In these culture system s, addition of exogenous TGF-beta downregulated basal and cytokine-induced proliferation of CLL-B cells. In contrast, neither neutralization of endoge neous TGF-beta, nor addition of exogeneous TGF-beta changed the proliferati on of CLL-B cells as cultured in the CD40 system. In order to further explo re this differential antiproliferative effect of TGF-beta, cytokine secreti on of B cells and of CD4(+) T cells as well as surface marker expression of CD4(+) T cells were assessed in relation to TGF-beta: There was no negativ e effect of TGF-beta on autocrine secretion of TNF-alpha or sCD23 by CLL-B cells. Unlike tonsillar B cells, CLL-B cells cultured alone or in the CD40 system did no release significant amounts of IL-6 or IL-8 into supernatants . Secretion of IL-2 or IL-4 by activated CD4(+) T cells was higher, when T cells were cocultured with normal tonsillar B cells than with CLL-B cells. The amount of IL-2 or IL-4 released by CD4(+) T cells cocultured in direct contact with tonsillar or CLL-B cells was not consistently influenced eithe r by neutralization of endogenous TGF-beta or by addition of TGF-beta. Exog enous TGF-beta did not downregulate expression of CD40L, CD27, CD28, CD54 o r mTNF-alpha by T helper cells activated with anti-CD3 or PHA. In conclusion, autocrine secretion of TGF-beta exhibits an antiproliferativ e effect on CLL-B cells. This effect is most relevant in B cells cultured i n direct contact with activated CD4(+) T cells suggesting an indirect mode of action.