title: Impaired Tax-specific T-cell responses with insufficient control of HTLV-1 in a subgroup of individuals at asymptomatic and smoldering stages.
abstract: Human T-cell leukemia virus type-1 (HTLV-1)-specific T-cell immunity, a potential antitumor surveillance system in vivo, is impaired in adult T-cell leukemia (ATL). In this study, we aimed to clarify whether the T-cell insufficiency in ATL is present before the disease onset or occurs as a consequence of the disease. We investigated T-cell responses against Tax protein in peripheral blood mononuclear cells (PBMCs) from individuals at earlier stages of HTLV-1-infection, including 21 asymptomatic HTLV-1 carriers (ACs) and four patients with smoldering-type ATL (sATL), whose peripheral lymphocyte count was in normal range. About 30% of samples tested showed clear Tax-specific interferon (IFN)-gamma producing responses. Proviral loads in this group were significantly lower than those in the other less-specific response group. The latter group was further divided to two subgroups with or without emergence of Tax-specific responses following depletion of CC chemokine receptor 4 (CCR4)(+) cells that contained HTLV-1-infected cells. In the PBMCs with Tax-specific responses, CD8(+) cells efficiently suppressed HTLV-1 p19 production in culture. The remaining group without the emergence of Tax-specific response after CCR4(+) cell-depletion included at least two sATL and one AC samples, which spontaneously produced HTLV-1 p19 in culture, where tetramer-binding, Tax-specific cytotoxic T-lymphocytes were either undetectable or unresponsive. Our results indicated that HTLV-1-specific T-cell responsiveness widely differed among HTLV-1 carriers, and that impairment of HTLV-1-specific T-cell responses was observed not only in advanced ATL patients but also in a subpopulation at earlier stages, which was associated with insufficient control of HTLV-1.
authors.affiliation: Department of Immunotherapeutics, Tokyo Medical and Dental University, Graduate School, Tokyo, Japan.
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Shimizu
authors.forename: Ayako
authors.initials: A
authors.lastname: Takamori
authors.forename: Atae
authors.initials: A
authors.lastname: Utsunomiya
authors.forename: Mayumi
authors.initials: M
authors.lastname: Kurimura
authors.forename: Yoshihisa
authors.initials: Y
authors.lastname: Yamano
authors.forename: Masakatsu
authors.initials: M
authors.lastname: Hishizawa
authors.forename: Atsuhiko
authors.initials: A
authors.lastname: Hasegawa
authors.forename: Fumiaki
authors.initials: F
authors.lastname: Kondo
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Kurihara
authors.forename: Nanae
authors.initials: N
authors.lastname: Harashima
authors.forename: Toshiki
authors.initials: T
authors.lastname: Watanabe
authors.forename: Jun
authors.initials: J
authors.lastname: Okamura
authors.forename: Takao
authors.initials: T
authors.lastname: Masuda
authors.forename: Mari
authors.initials: M
authors.lastname: Kannagi
mesh_terms: D000328:Adult; D000368:Aged; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D016356:Gene Products, tax / Q000276:immunology*; D015490:HTLV-I Infections / Q000276:immunology* / Q000821:virology; D015368:Human T-lymphotropic virus 1 / Q000276:immunology; D006801:Humans; D007157:Immunologic Surveillance; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000276:immunology* / Q000821:virology; D008297:Male; D008875:Middle Aged; D054398:Receptors, CCR4 / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
chemical_list: C515354:CCR4 protein, human; D016356:Gene Products, tax; D054398:Receptors, CCR4