title: Tax-inducible production of CC chemokine ligand 22 by human T cell leukemia virus type 1 (HTLV-1)-infected T cells promotes preferential transmission of HTLV-1 to CCR4-expressing CD4+ T cells.
abstract: Adult T cell leukemia is a mature CD4+ T cell malignancy which predominantly expresses CCR4 and is etiologically associated with human T cell leukemia virus type 1 (HTLV-1). Because HTLV-1 transmission depends on close cell-cell contacts, HTLV-1-infected T cells may preferentially interact with CCR4+CD4+ T cells for efficient viral transmission. In terms of gene expression and protein secretion, we found a strong correlation between HTLV-1 Tax oncoprotein and CCL22, a CCR4 ligand, in HTLV-1-infected T cells. Transient Tax expression in an HTLV-1-negative T cell line activated the CCL22 promoter and induced CCL22. Additionally, tax gene knockdown by small interference RNA reduced CCL22 expression in the infected T cells. These findings indicate that CCL22 is a cellular target gene of Tax. In chemotaxis assays, the culture supernatants of HTLV-1-infected T cells selectively attracted CCR4+CD4+ T cells in PBMCs. This was blocked by pretreating the supernatants with anti-CCL22 Ab or PBMCs with a synthetic CCR4 antagonist. In coculture experiments, primary CCR4+CD4+ T cells significantly adhered to Tax-expressing cells. This adhesion was blocked by the CCR4 antagonist or pertussis toxin. Interestingly, CCR4 was redistributed to the contact region, and in some cases, this was accompanied by a polarized microtubule-organizing center, which is an indicator of virological synapse formation, in the infected T cells. Finally, anti-CCL22 Ab treatment also blocked HTLV-1 transmission to primary CD4+ T cells in coculture experiments with HTLV-1 producer cells. Thus, HTLV-1-infected T cells produce CCL22 through Tax and selectively interact with CCR4+CD4+ T cells, resulting in preferential transmission of HTLV-1 to CCR4+CD4+ T cells.
authors.affiliation: Department of Microbiology, Kinki University School of Medicine, Osaka-Sayama, Osaka, Japan. hieshima@med.kindai.ac.jp
authors.forename: Kunio
authors.initials: K
authors.lastname: Hieshima
authors.forename: Daisuke
authors.initials: D
authors.lastname: Nagakubo
authors.forename: Takashi
authors.initials: T
authors.lastname: Nakayama
authors.forename: Aiko-Konno
authors.initials: AK
authors.lastname: Shirakawa
authors.forename: Zhe
authors.initials: Z
authors.lastname: Jin
authors.forename: Osamu
authors.initials: O
authors.lastname: Yoshie
mesh_terms: D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000821:virology*; D002448:Cell Adhesion / Q000187:drug effects / Q000235:genetics; D002460:Cell Line; D054422:Chemokine CCL22 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D015967:Gene Expression Regulation, Viral; D016356:Gene Products, tax / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015368:Human T-lymphotropic virus 1 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D037342:Pertussis Toxin / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D054398:Receptors, CCR4 / Q000037:antagonists & inhibitors / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology / Q000821:virology; D053586:Virus Internalization
chemical_list: C515482:CCL22 protein, human; C515354:CCR4 protein, human; D054422:Chemokine CCL22; D016356:Gene Products, tax; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D054398:Receptors, CCR4; D037342:Pertussis Toxin