Clonal Th2 cells associated with chronic hypereosinophilia: TARC-induced CCR4 down-regulation in vivo

We analyzed the expression of chemokine receptors on clonal Th2-type CD4(+) CD3(-) lymphocytes isolated from blood of two patients with chronic hypereo sinophilia. First, we observed that these Th2 cells express membrane CCR5 a nd CXCR4 but neither CCR3 nor CCR4 when analyzed immediately after purifica tion. 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 cultur ed Th2 cells. As high levels of TARC, a CCR4 ligand, were detected in the s erum of four hyper eosinophilic patients with CD3(-)CD4(+) clonal Th2 cells , we evaluated the effect of TARC neutralization in this system. Addition o f a neutralizing anti-TARC mAb inhibited CCR4 downregulation by patient's s erum, indicating that circulating TARC contributed to CCR4 downregulation o n Th2 cells in vivo. Clonal Th2 cells did not secrete high levels of TARC t hemselves but induced a sustained production of TARC by monocyte-derived de ndritic 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-regu lation of CCR4 on Th2 cells in vivo.