Kehrl J H, Roberts A B, Wakefield L M, Jakowlew S, Sporn M B, Fauci A S
J Immunol. 1986 Dec 15;137(12):3855-60.
The growth and differentiation of B cells to immunoglobulin (Ig)-secreting cells is regulated by a variety of soluble factors. This study presents data that support a role for transforming growth factor (TGF)-beta in this regulatory process. B lymphocytes were shown to have high-affinity receptors for TGF-beta that were increased fivefold to sixfold after in vitro activation. The addition of picogram quantities of TGF-beta to B cell cultures suppressed factor-dependent, interleukin 2 (IL 2) B cell proliferation and markedly suppressed factor-dependent (IL 2 or B cell differentiation factor) B cell Ig secretion. In contrast, the constitutive IgG production by an Epstein Barr virus-transformed B cell line was not modified by the presence of TGF-beta in culture. This cell line was found to lack high-affinity TGF-beta receptors. The degree of inhibition of B cell proliferation observed in in vitro cultures was found to be dependent not only on the concentration of TGF-beta added but also on the concentration of the growth stimulatory substance (IL 2) present. By increasing the IL 2 concentrations in culture, the inhibition of proliferation induced by TGF-beta could be partially overcome. In contrast, the inhibition of Ig secretion induced by TGF-beta could not be overcome by a higher concentration of stimulatory factor, demonstrating that the suppression of B cell differentiation by TGF-beta is not due solely to its effects on proliferation. Furthermore, it was demonstrated that B lymphocytes secrete TGF-beta. Unactivated tonsillar B cells had detectable amounts of TGF-beta mRNA on Northern blot analysis, and B cell activation with Staphylococcus aureus Cowan (SAC) resulted in a twofold to threefold increase in TGF-beta mRNA. Supernatants conditioned by unactivated B cells had small amounts of TGF-beta, SAC activation of the B cells resulted in a sixfold to sevenfold increase in the amount of TGF-beta present in the supernatants. Thus, B lymphocytes synthesize and secrete TGF-beta and express receptors for TGF-beta. The addition of exogenous TGF-beta to cultures of stimulated B cells inhibits subsequent proliferation and Ig secretion. TGF-beta may function as an autocrine growth inhibitor that limits B lymphocyte proliferation and ultimate differentiation.
B细胞向分泌免疫球蛋白（Ig）细胞的生长和分化受多种可溶性因子调控。本研究提供的数据支持转化生长因子（TGF）-β在这一调控过程中发挥作用。研究表明，B淋巴细胞具有TGF-β的高亲和力受体，体外激活后其数量增加5至6倍。向B细胞培养物中添加皮克量的TGF-β可抑制因子依赖性的白细胞介素2（IL 2）介导的B细胞增殖，并显著抑制因子依赖性（IL 2或B细胞分化因子）的B细胞Ig分泌。相反，爱泼斯坦-巴尔病毒转化的B细胞系组成性产生的IgG不受培养物中TGF-β存在的影响。发现该细胞系缺乏高亲和力的TGF-β受体。体外培养中观察到的B细胞增殖抑制程度不仅取决于添加的TGF-β浓度，还取决于存在的生长刺激物质（IL 2）的浓度。通过提高培养物中IL 2的浓度，可部分克服TGF-β诱导的增殖抑制。相反，更高浓度的刺激因子无法克服TGF-β诱导的Ig分泌抑制，这表明TGF-β对B细胞分化的抑制并非仅仅归因于其对增殖的影响。此外，研究表明B淋巴细胞分泌TGF-β。未激活的扁桃体B细胞在Northern印迹分析中有可检测到的TGF-β mRNA量，用金黄色葡萄球菌Cowan株（SAC）激活B细胞导致TGF-β mRNA增加2至3倍。未激活B细胞条件培养液中有少量TGF-β，B细胞经SAC激活后，培养液中TGF-β的量增加6至7倍。因此，B淋巴细胞合成并分泌TGF-β并表达TGF-β受体。向受刺激的B细胞培养物中添加外源性TGF-β可抑制随后的增殖和Ig分泌。TGF-β可能作为一种自分泌生长抑制剂，限制B淋巴细胞的增殖和最终分化。
