Human T-lymphotropic virus type 1-induced CC chemokine ligand 22 maintains a high frequency of functional FoxP3+ regulatory T cells.
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.
Department of Immunology, Barts and The London School of Medicine and Dentistry, London, United Kingdom. f.toulza@imperial.ac.uk
Frederic
F
Toulza
Kisato
K
Nosaka
Yuetsu
Y
Tanaka
Tiziana
T
Schioppa
Frances
F
Balkwill
Graham P
GP
Taylor
Charles R M
CR
Bangham
D018791:CD4 Lymphocyte Count; D049109:Cell Proliferation; D002470:Cell Survival / Q000276:immunology; D054422:Chemokine CCL22 / Q000096:biosynthesis / Q000097:blood / Q000502:physiology*; D003601:Cytotoxicity Tests, Immunologic; D051858:Forkhead Transcription Factors / Q000096:biosynthesis / Q000097:blood / Q000502:physiology*; D015490:HTLV-I Infections / Q000276:immunology / Q000473:pathology; D015368:Human T-lymphotropic virus 1 / Q000276:immunology*; D006801:Humans; D019169:Jurkat Cells; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000276:immunology / Q000473:pathology; D013602:T-Lymphocytes, Cytotoxic / Q000166:cytology / Q000276:immunology / Q000821:virology; D050378:T-Lymphocytes, Regulatory / Q000166:cytology* / Q000276:immunology* / Q000821:virology
C515482:CCL22 protein, human; D054422:Chemokine CCL22; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors