Production of thymus and activation-regulated chemokine and macrophage-derived chemokine by CCR4+ adult T-cell leukemia cells.
OBJECTIVE
Adult T-cell leukemia/lymphoma (ATL) is a peripheral CD4(+)CD25(+) T-cell malignancy caused by human T-cell leukemia virus type I. The tumor cells frequently infiltrate in the skin, lymph nodes and other organs and especially form prominent cutaneous masses. Recently, ATL cells have been shown to express Th2 chemokine receptor CCR4. The aim of this study is to investigate the possibility that CCR4 ligands, thymus and activation-regulated chemokine (TARC) and macrophage-derived chemokine (MDC), are produced by CCR4(+) ATL cells per se.


METHODS
CD4(+) or CD4(+)CD14(-) cells were purified from peripheral blood mononuclear cells of 11 ATL patients with cutaneous involvement and normal healthy volunteers. Tissue-infiltrating cells were isolated from skin tumors. The expression of chemokine receptors on these cells were analyzed by flow cytometry. The production of chemokines and cytokines by the neoplastic cells was assessed by ELISA and reverse transcription-PCR after cultivation for 96 hours in the presence or absence of anti-CD3/CD28 monoclonal antibodies. Finally, TARC and CCR4 expressions were examined by immunohistochemistry.


RESULTS
ATL cells highly expressed CCR4 but did not necessarily exhibit the Th2 cytokine profile. The cells also produced TARC and MDC. The production level of MDC was higher in the skin tumor formation group than that in the nontumor group. Immunohistochemically, both CCR4 and TARC were expressed by the tumor cells in the lesional skin.


CONCLUSIONS
ATL cells not only express CCR4 but also produce TARC and MDC. The skin tumor formation as well as the monoclonal integration of proviral DNA are the factors that are associated with the high production of Th2 chemokines by ATL cells.
Shimauchi
Takatoshi
T
Department of Dermatology, University of Occupational and Environmental Health, 1-1 Iseogaoka, Yahatanishi-ku, Kitakyusyu 807-8555, Japan. t-shima@med.uoeh-u.ac.jp
Imai
Satoshi
S
Hino
Ryosuke
R
Tokura
Yoshiki
Y
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal; D001666:Binding Sites, Antibody; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D054422:Chemokine CCL22; D019742:Chemokines, CC / Q000276:immunology / Q000378:metabolism; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D008024:Ligands; D008297:Male; D008875:Middle Aged; D054398:Receptors, CCR4; D019707:Receptors, Chemokine / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012878:Skin Neoplasms / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D018418:Th2 Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D013950:Thymus Gland / Q000276:immunology* / Q000378:metabolism
D000911:Antibodies, Monoclonal; C515482:CCL22 protein, human; C515354:CCR4 protein, human; D054422:Chemokine CCL22; D019742:Chemokines, CC; D016207:Cytokines; D008024:Ligands; D054398:Receptors, CCR4; D019707:Receptors, Chemokine