TGF-β Down-Regulates Stromal IL-7 Secretion and Inhibits Proliferation of Human B Cell Precursors

Development of lymphoid progenitors in vivo requires interaction with a bone marrow stromal microenvironment containing multiple cytokines involved in the development of nonlymphoid hemopoietic lineages. We tested the effect of one such cytokine, TGF-β, on the proliferation of early human clonogenic lymphoid progenitors using a stroma-dependent in vitro culture system. TGF-β caused a dose-dependent inhibition of lymphoid progenitor colonies that was reversible at low TGF-β doses by addition of exogenous IL-7 to the cultures. IL-7 was unable to reverse the inhibitory effect of higher TGF-β concentrations or inhibition caused by IL-1α, IL-4, or TNF-α. Stromal IL-7 mRNA expression and protein secretion were markedly down-regulated by TGF-β, suggesting that inhibition of stromal IL-7 secretion partially accounts for the inhibitory effect of TGF-β on lymphopoiesis in this culture system. It is likely that higher TGF-β concentrations do not inhibit lymphopoiesis by down-regulating IL-7 receptor expression, since this cytokine did not reduce IL-7Rα or γc mRNA levels in normal B cell precursors. Since direct stromal contact is required for in vitro lymphopoiesis, the potential regulation of the IL-7 pathway by cell adhesion was examined. Adhesion of human B cell precursors to stroma did not alter stromal IL-7 expression or expression of IL-7Rα or γc-chains by B cell precursors. These results indicate that TGF-β is a significant negative regulator of stroma-dependent proliferation of early human lymphoid progenitors and acts in part by down-regulating stromal IL-7 secretion.