Transforming growth factor-β regulates normal human pre-B cell differentiation

Light chain gene rearrangement during mammalian pre-B differentiation generally occurs in an orderly manner, beginning with χ genes and proceeding through λ genes. We have previously shown that human pre-B cell differentiation in vitro leads to a skewing toward χ expression, resulting in a higher percentage of λ⁺ cells than χ⁺ cells. We now report that the multifunctional polypeptlde transforming growth factor-β (TGF-β) exerts a selective inhibitory effect on the acquisition of cell surface λ light chains during in vitro differentiation of normal human pre-B cells, giving rise to a balanced ratio (∼1:1) of χ⁺ to λ⁺ cells that resembles what normally exists in vivo. The TGF-β effect was ablated using a neutralizing antl-TGF-β antlserum and TGF-β had no significant effect on the acquisition of χ or surrogate light chains. Experiments using highly enriched pre-B cells (90-95% cytoplasmlc μ⁺) suggested that the TGF-β effect was directly on the pre-B cell or the pre-B cell to μ⁺/λ⁺ Immature B cell transition. The following peptldes, cytoklnes, and antibodies had no effect on light chain acquisition or expression: substance P, vasoactlve intestinal peptlde, leu/met enkephalin, IL-1, IL-4, IL-7, anti-class II MHC, antl-CD24, antl-CD40, and the CD10 inhibitor phosphoramldon. A selective regulatory role for TGF-β on normal human B cell development in the bone marrow mlcroenvlronment Is suggested by these results.