Ranheim E A, Cantwell M J, Kipps T J
Department of Medicine, University of California San Diego, La Jolla 92093-0663, USA.
Blood. 1995 Jun 15;85(12):3556-65.
Crosslinking the CD27 antigen on T cells provides a costimulatory signal that, in concert with T-cell receptor crosslinking, can induce T-cell proliferation and cellular immune activation. We find that chronic lymphocytic leukemia (CLL) B cells from most patients coexpress both membrane-bound and soluble CD27, along with its newly identified ligand, CD70. The expression of soluble CD27 may preclude leukemic B cells from stimulating T cells via CD70, thereby potentially impairing their ability to function as effective antigen-presenting cells. We find that leukemic B-cell expression of soluble and membrane-bound CD27 can be downmodulated through a CD40-dependent signal. This signal also induces enhanced expression of CD70 on both normal and leukemic B cells. We find that tumor necrosis factor (TNF)-alpha, or the Th1 cytokine interferon (IFN)-gamma, also can induce downmodulation of CD27, whereas Th2-associated cytokines interleukin-4 (IL-4) or IL-10 can enhance leukemic B-cell expression of this accessory molecule. The modulation of CD27 induced by these conditions is accompanied by reciprocal changes in the expression levels of CD70, suggesting that these accessory molecules may be engaged in reciprocal receptor-ligand downmodulation. Consistent with this, we observe that co-culture of CLL B cells with transfected murine plasmacytoma cells that express human CD70 affects downmodulation of CD27 and enhanced expression of CD70 on leukemic B cells, but does not affect expression of CD27 mRNA. However, we find that CD40-crosslinking, in addition to reducing the level of CD27 protein, also reduces leukemic B-cell expression of CD27 mRNA. This argues that the changes in the expression levels of CD27 following CD40-signaling are not simply due to induced increases in the expression levels of CD70. Finally, we demonstrate that reciprocal changes in expression of CD27 and CD70 may contribute to the enhanced antigen-presenting capacity of CLL B cells after CD40-dependent leukemic B-cell activation. These findings expand the understanding of the regulation of costimulatory molecules important in antigen presentation and also have implications for the immunobiology of and therapy for CLL.
交联T细胞上的CD27抗原可提供共刺激信号，该信号与T细胞受体交联协同作用，可诱导T细胞增殖和细胞免疫激活。我们发现，大多数患者的慢性淋巴细胞白血病（CLL）B细胞同时共表达膜结合型和可溶性CD27及其新发现的配体CD70。可溶性CD27的表达可能会阻止白血病B细胞通过CD70刺激T细胞，从而潜在地损害其作为有效抗原呈递细胞的功能。我们发现，可溶性和膜结合型CD27在白血病B细胞中的表达可通过CD40依赖性信号下调。该信号还可诱导正常和白血病B细胞上CD70的表达增强。我们发现，肿瘤坏死因子（TNF）-α或Th1细胞因子干扰素（IFN）-γ也可诱导CD27下调，而Th2相关细胞因子白细胞介素-4（IL-4）或IL-10可增强白血病B细胞中这种辅助分子的表达。这些条件诱导的CD27调节伴随着CD70表达水平的相互变化，表明这些辅助分子可能参与了受体-配体的相互下调。与此一致的是，我们观察到CLL B细胞与表达人CD70的转染鼠浆细胞瘤细胞共培养会影响白血病B细胞上CD27的下调和CD70表达的增强，但不影响CD27 mRNA的表达。然而，我们发现CD40交联除了降低CD27蛋白水平外，还会降低白血病B细胞中CD27 mRNA的表达。这表明CD40信号传导后CD27表达水平的变化不仅仅是由于CD70表达水平的诱导增加。最后，我们证明CD27和CD70表达的相互变化可能有助于CD40依赖性白血病B细胞激活后CLL B细胞抗原呈递能力的增强。这些发现扩展了我们对在抗原呈递中重要的共刺激分子调节的理解，也对CLL的免疫生物学和治疗具有重要意义。
