Ranheim E A, Kipps T J
Department of Medicine, University of California, San Diego, La Jolla 92093-0663.
Cell Immunol. 1995 Apr 1;161(2):226-35. doi: 10.1006/cimm.1995.1031.
Expression of immune accessory molecules, such as CD80 (B7-1), on antigen-presenting cells governs whether such cells can activate antigen-specific T cells. As such, the factors that regulate the expression of these accessory molecules may determine whether presentation of antigen leads to immune activation or anergy. We previously reported that anti-CD3-activated T cells (Ta) can induce expression of CD80 and CD54 (ICAM-1) on human B cells through a contact-dependent signal delivered to the CD40 molecule via the CD40 ligand. Here, we demonstrate that another molecule in the CD40-ligand family, namely tumor necrosis factor-alpha (TNF-alpha), also plays a role in the Ta-mediated induction of CD80 or CD54 on human B cells. Neutralizing mAbs specific for TNF-alpha can inhibit B cell expression of CD80 or CD54 that is induced when B cells are cultured with Ta cells or in Ta-cell conditioned media. Moreover, soluble, recombinant TNF-alpha or TNF-beta can induce significant increases in B cell expression of CD80 and CD54. The phenotypic changes effected by TNF-alpha can be recapitulated by crosslinking CD120b (p75 TNF-receptor), but not CD120a (p55 TNF-receptor), with mAbs presented on Fc gamma RII (CD32)-expressing L cells. IL-4 augments the expression of CD80 induced by crosslinking either CD40 or CD120b. However, although IL-10 augments CD40-induced expression of CD80, this cytokine inhibits the expression of CD80 that is induced by crosslinking CD120b. Further regulation of TNF-mediated CD80 expression may occur at the level of CD120b expression itself. We find that stimulation with exogenous IL-4 or CD40-cross-linking induces B cell expression of CD120b, but not CD120a. This study identifies an ancillary, TNF-mediated pathway, whereby activated T cells can induce B cells to express enhanced levels of the important costimulatory molecules, CD80 and CD54.
抗原呈递细胞上免疫辅助分子（如CD80（B7-1））的表达决定了这些细胞是否能够激活抗原特异性T细胞。因此，调节这些辅助分子表达的因素可能决定抗原呈递是否会导致免疫激活或无反应性。我们之前报道过，抗CD3激活的T细胞（Ta）可通过经由CD40配体传递至CD40分子的接触依赖性信号，诱导人B细胞上CD80和CD54（细胞间黏附分子-1）的表达。在此，我们证明CD40配体家族中的另一种分子，即肿瘤坏死因子-α（TNF-α），在Ta介导的人B细胞上CD80或CD54的诱导过程中也发挥作用。针对TNF-α的中和单克隆抗体可抑制B细胞上CD80或CD54的表达，这种表达是在B细胞与Ta细胞共培养或在Ta细胞条件培养基中培养时诱导产生的。此外，可溶性重组TNF-α或TNF-β可显著增加B细胞上CD80和CD54的表达。TNF-α所引起的表型变化可通过用表达FcγRII（CD32）的L细胞上呈现的单克隆抗体交联CD120b（p75 TNF受体）来重现，但不能通过交联CD120a（p55 TNF受体）来重现。IL-4增强了交联CD40或CD120b所诱导的CD80表达。然而，尽管IL-10增强了CD40诱导的CD80表达，但这种细胞因子抑制了交联CD120b所诱导的CD80表达。TNF介导的CD80表达的进一步调节可能发生在CD120b表达本身的水平。我们发现，用外源性IL-4刺激或CD40交联可诱导B细胞表达CD120b，但不表达CD120a。本研究确定了一条辅助性的、TNF介导的途径，通过该途径活化的T细胞可诱导B细胞表达更高水平的重要共刺激分子CD80和CD54。
