Miyashita T, McIlraith M J, Grammer A C, Miura Y, Attrep J F, Shimaoka Y, Lipsky P E
Harold C. Simmons Arthritis Research Center, Department of Internal Medicine, University of Texas Southwestern Medical Center at Dallas, 75235, USA.
J Immunol. 1997 May 15;158(10):4620-33.
Positive and negative effects of CD40 ligation on human B cell function were suggested by the observation that mAb to CD40 ligand partially blocked the suppressive influences of anti-CD3-stimulated control CD4+ T cells, as well as the B cell stimulatory effects of anti-CD3 activated mitomycin C-treated CD4+ T cells. To examine the negative effects of CD40 ligation in greater detail, B cells were cultured with anti-CD3 activated mitomycin C-treated CD4+ T cells that expressed optimal levels of CD40 ligand; additional recombinant human CD40 ligand significantly suppressed Ig production, but not proliferation. In contrast, when B cells were stimulated with SAC (formalinized Cowan I strain Staphylococcus aureus) and IL-2 in the absence of T cells, small amounts of recombinant CD40 ligand-stimulated Ig production, whereas larger quantities directly suppressed Ig secretion. The suppressive action of CD40 ligation on Ig production was most apparent after initial B cell activation. Moreover, IgD-memory B cells were significantly more sensitive to inhibition by CD40 ligation than IgD+ naive B cells. Engagement of CD40 not only suppressed Ig secretion by IgD- memory B cells, but also expression of CD38. Finally, activated B cells acquired the capacity to down-regulate CD40 ligand expression by stimulated CD4+ T cells more effectively than resting B cells. These results indicate that during T cell-B cell collaboration, engagement of CD40 can influence Ig production both positively and negatively, depending on the density of CD40 ligand as well as the stage of B cell activation and differentiation.
CD40连接对人B细胞功能的正负效应由以下观察结果提示：抗CD40配体单克隆抗体部分阻断了抗CD3刺激的对照CD4+T细胞的抑制作用，以及抗CD3激活的丝裂霉素C处理的CD4+T细胞的B细胞刺激作用。为了更详细地研究CD40连接的负面效应，将B细胞与表达最佳水平CD40配体的抗CD3激活的丝裂霉素C处理的CD4+T细胞一起培养；额外的重组人CD40配体显著抑制了Ig产生，但不影响增殖。相反，当在无T细胞的情况下用SAC（甲醛化考恩I株金黄色葡萄球菌）和IL-2刺激B细胞时，少量重组CD40配体刺激Ig产生，而大量则直接抑制Ig分泌。CD40连接对Ig产生的抑制作用在B细胞初始激活后最为明显。此外，IgD记忆B细胞比IgD+幼稚B细胞对CD40连接的抑制作用明显更敏感。CD40的结合不仅抑制了IgD记忆B细胞的Ig分泌，还抑制了CD38的表达。最后，活化的B细胞比静止的B细胞更有效地获得了下调受刺激CD4+T细胞CD40配体表达的能力。这些结果表明，在T细胞-B细胞协作过程中，CD40的结合可根据CD40配体的密度以及B细胞激活和分化的阶段对Ig产生产生正向和负向影响。
