title: HTLV-1 Viral Factor HBZ Induces CCR4 to Promote T-cell Migration and Proliferation.
abstract: Human T-cell leukemia virus type 1 (HTLV-1) causes adult T-cell leukemia-lymphoma (ATL) and other inflammatory diseases in infected individuals. However, a complete understanding of how HTLV-1 transforms T cells is lacking. Expression of the chemokine receptor CCR4 on ATL cells and HTLV-1-infected cells suggested the hypothesis that CCR4 may mediate features of ATL and inflammatory diseases caused by HTLV-1. In this study, we show that the constitutively expressed HTLV-1 bZIP factor (HBZ) encoded by HTLV-1 is responsible for inducing CCR4 and its ability to promote T-cell proliferation and migration. Ectopic expression of HBZ was sufficient to stimulate expression of CCR4 in human and mouse T cells. Conversely, HBZ silencing in ATL cell lines was sufficient to inhibit CCR4 expression. Mechanistic investigations showed that HBZ induced GATA3 expression in CD4(+) T cells, thereby activating transcription from the CCR4 promoter. In an established air pouch model of ATL, we observed that CD4(+) T cells of HBZ transgenic mice (HBZ-Tg mice) migrated preferentially to the pouch, as compared with those in nontransgenic mice. Migration of CD4(+) T cells in HBZ-Tg mice was inhibited by treatment with a CCR4 antagonist. Proliferating (Ki67(+)) CD4(+) T cells were found to express high levels of CCR4 and CD103. Further, CD4(+) T-cell proliferation in HBZ-Tg mice was enhanced by coordinate treatment with the CCR4 ligands CCL17 and 22 and with the CD103 ligand E-cadherin. Consistent with this finding, we found that ATL cells in clinical skin lesions were frequently positive for CCR4, CD103, and Ki67. Taken together, our results show how HBZ activates CCR4 expression on T cells to augment their migration and proliferation, two phenomena linked to HTLV-1 pathogenesis. Cancer Res; 76(17); 5068-79. ©2016 AACR.
authors.affiliation: Laboratory of Virus Control, Institute for Virus Research, Kyoto University, Kyoto, Japan. Japan Society for the Promotion of Science (JSPS), Tokyo, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Sugata
authors.affiliation: Laboratory of Virus Control, Institute for Virus Research, Kyoto University, Kyoto, Japan.
authors.forename: Jun-Ichirou
authors.initials: J
authors.lastname: Yasunaga
authors.affiliation: Laboratory of Virus Control, Institute for Virus Research, Kyoto University, Kyoto, Japan.
authors.forename: Haruka
authors.initials: H
authors.lastname: Kinosada
authors.affiliation: Laboratory of Virus Control, Institute for Virus Research, Kyoto University, Kyoto, Japan.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Mitobe
authors.affiliation: Laboratory of Virus Control, Institute for Virus Research, Kyoto University, Kyoto, Japan.
authors.forename: Rie
authors.initials: R
authors.lastname: Furuta
authors.affiliation: Laboratory of Virus Control, Institute for Virus Research, Kyoto University, Kyoto, Japan.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Mahgoub
authors.affiliation: Laboratory of Virus Control, Institute for Virus Research, Kyoto University, Kyoto, Japan.
authors.forename: Chiho
authors.initials: C
authors.lastname: Onishi
authors.affiliation: Department of Pathology, School of Medicine, Kurume University, Kurume, Japan.
authors.forename: Kazutaka
authors.initials: K
authors.lastname: Nakashima
authors.affiliation: Department of Pathology, School of Medicine, Kurume University, Kurume, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Ohshima
authors.affiliation: Laboratory of Virus Control, Institute for Virus Research, Kyoto University, Kyoto, Japan. mmatsuok@virus.kyoto-u.ac.jp.
authors.forename: Masao
authors.initials: M
authors.lastname: Matsuoka
mesh_terms: D000818:Animals; D050976:Basic-Leucine Zipper Transcription Factors / Q000378:metabolism*; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism / Q000821:virology*; D049109:Cell Proliferation / Q000502:physiology; D002472:Cell Transformation, Viral; D002634:Chemotaxis, Leukocyte / Q000502:physiology; D050990:GATA3 Transcription Factor / Q000378:metabolism; D015967:Gene Expression Regulation, Viral; D015490:HTLV-I Infections / Q000378:metabolism*; D015368:Human T-lymphotropic virus 1; D006801:Humans; D007150:Immunohistochemistry; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000378:metabolism / Q000473:pathology*; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D054398:Receptors, CCR4 / Q000378:metabolism*; D012191:Retroviridae Proteins / Q000378:metabolism*
chemical_list: D050976:Basic-Leucine Zipper Transcription Factors; D050990:GATA3 Transcription Factor; C479751:HBZ protein, human T-cell leukemia virus type I; D054398:Receptors, CCR4; D012191:Retroviridae Proteins