Human T-Lymphotropic Virus Type 1-Induced CC Chemokine Ligand 22 Maintains a High Frequency of Functional FoxP3+ Regulatory T Cells

Abstract

We recently reported that human T-lymphotropic virus type 1 (HTLV-1) infection is accompanied by a high frequency of CD4+FoxP3+ cells in the circulation. In asymptomatic carriers of HTLV-1 and in patients with HTLV-1–associated inflammatory and malignant diseases, a high FoxP3+ cell frequency correlated with inefficient cytotoxic T cell-mediated killing of HTLV-1–infected cells. In adult T cell leukemia/lymphoma (ATLL), the FoxP3+ population was distinct from the leukemic T cell clones. However, the cause of the increase in FoxP3+ cell frequency in HTLV-1 infection was unknown. In this study, we report that the plasma concentration of the chemokine CCL22 is abnormally high in HTLV-1–infected subjects and that the concentration is strongly correlated with the frequency of FoxP3+ cells, which express the CCL22 receptor CCR4. Further, we show that CCL22 is produced by cells that express the HTLV-1 transactivator protein Tax, and that the increased CCL22 enhances the migration and survival of FoxP3+ cells in vitro. Finally, we show that FoxP3+ cells inhibit the proliferation of ex vivo, autologous leukemic clones from patients with ATLL. We conclude that HTLV-1–induced CCL22 causes the high frequency of FoxP3+ cells observed in HTLV-1 infection; these FoxP3+ cells may both retard the progression of ATLL and HTLV-1–associated inflammatory diseases and contribute to the immune suppression seen in HTLV-1 infection, especially in ATLL.