de Lavareille A, Roufosse F, Schandené L, Stordeur P, Cogan E, Goldman M
Department of Immunology-Hematology-Transfusion, Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium.
Eur J Immunol. 2001 Apr;31(4):1037-46. doi: 10.1002/1521-4141(200104)31:4<1037::aid-immu1037>3.0.co;2-#.
We analyzed the expression of chemokine receptors on clonal Th2-type CD4(+)CD3(- )lymphocytes isolated from blood of two patients with chronic hypereosinophilia. First, we observed that these Th2 cells express membrane CCR5 and CXCR4 but neither CCR3 nor CCR4 when analyzed immediately after purification. However, CCR4 appeared following culture in human serum-free medium, suggesting that it was down-regulated in vivo. Indeed, patient's serum, but not control human serum, strongly down-regulated CCR4 expression on cultured Th2 cells. As high levels of TARC, a CCR4 ligand, were detected in the serum of four hypereosinophilic patients with CD3(-)CD4(+) clonal Th2 cells, we evaluated the effect of TARC neutralization in this system. Addition of a neutralizing anti-TARC mAb inhibited CCR4 down-regulation by patient's serum, indicating that circulating TARC contributed to CCR4 down-regulation on Th2 cells in vivo. Clonal Th2 cells did not secrete high levels of TARC themselves but induced a sustained production of TARC by monocyte-derived dendritic cells, a phenomenon that was inhibited by addition of blocking mAb against IL-4 receptor. We conclude that high circulating levels of TARC in serum of patients with chronic hypereosinophilia, most likely derived from antigen-presenting cells stimulated by Th2-type cytokines, induce down-regulation of CCR4 on Th2 cells in vivo.
我们分析了从两名慢性嗜酸性粒细胞增多症患者血液中分离出的克隆性Th2型CD4(+)CD3(-)淋巴细胞上趋化因子受体的表达情况。首先，我们观察到这些Th2细胞在纯化后立即分析时表达膜型CCR5和CXCR4，但不表达CCR3和CCR4。然而，在无血清培养基中培养后CCR4出现了，这表明它在体内被下调。实际上，患者血清而非对照人血清能强烈下调培养的Th2细胞上CCR4的表达。由于在四名患有CD3(-)CD4(+)克隆性Th2细胞的嗜酸性粒细胞增多症患者血清中检测到高水平的CCR4配体TARC，我们评估了TARC中和在该系统中的作用。添加中和性抗TARC单克隆抗体可抑制患者血清对CCR4的下调作用，这表明循环中的TARC在体内促成了Th2细胞上CCR4的下调。克隆性Th2细胞本身不分泌高水平的TARC，但可诱导单核细胞来源的树突状细胞持续产生TARC，这一现象可被添加抗IL-4受体阻断单克隆抗体所抑制。我们得出结论，慢性嗜酸性粒细胞增多症患者血清中高水平的循环TARC，很可能源自受Th2型细胞因子刺激的抗原呈递细胞，在体内诱导Th2细胞上CCR4的下调。
