title: Functional impairment of Tax-specific but not cytomegalovirus-specific CD8+ T lymphocytes in a minor population of asymptomatic human T-cell leukemia virus type 1-carriers.
abstract: BACKGROUND
  Human T-cell leukemia virus type 1 (HTLV-1) causes adult T-cell leukemia (ATL) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) in a small percentage of infected individuals. ATL is often associated with general immune suppression and an impaired HTLV-1-specific T-cell response, an important host defense system. We previously found that a small fraction of asymptomatic HTLV-1-carriers (AC) already showed impaired T-cell responses against the major target antigen, Tax. However, it is unclear whether the impaired HTLV-1 Tax-specific T-cell response in these individuals is an HTLV-1-specific phenomenon, or merely reflects general immune suppression. In this study, in order to characterize the impaired HTLV-1-specific T-cell response, we investigated the function of Tax-specific CD8+ T-cells in various clinical status of HTLV-1 infection.
  
  
  RESULTS
  By using tetramers consisting of HLA-A*0201, -A*2402, or -A*1101, and corresponding Tax epitope peptides, we detected Tax-specific CD8+ T-cells in the peripheral blood from 87.0% of ACs (n = 20/23) and 100% of HAM/TSP patients (n = 18/18) tested. We also detected Tax-specific CD8+ T-cells in 38.1% of chronic type ATL (cATL) patients (n = 8/21), although its frequencies in peripheral blood CD8+ T cells were significantly lower than those of ACs or HAM/TSP patients. Tax-specific CD8+ T-cells detected in HAM/TSP patients proliferated well in culture and produced IFN-γ when stimulated with Tax peptides. However, such functions were severely impaired in the Tax-specific CD8+ T-cells detected in cATL patients. In ACs, the responses of Tax-specific CD8+ T-cells were retained in most cases. However, we found one AC sample whose Tax-specific CD8+ T-cells hardly produced IFN-γ, and failed to proliferate and express activation (CD69) and degranulation (CD107a) markers in response to Tax peptide. Importantly, the same AC sample contained cytomegalovirus (CMV) pp65-specific CD8+ T-cells that possessed functions upon CMV pp65 peptide stimulation. We further examined additional samples of two smoldering type ATL patients and found that they also showed dysfunctions of Tax-specific but not CMV-specific CD8+ T-cells.
  
  
  CONCLUSIONS
  These findings indicated that Tax-specific CD8+ T-cells were scarce and dysfunctional not only in ATL patients but also in a limited AC population, and that the dysfunction was selective for HTLV-1-specifc CD8+ T-cells in early stages.
authors.affiliation: Department of Immunotherapeutics, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Ayako
authors.initials: A
authors.lastname: Takamori
authors.forename: Atsuhiko
authors.initials: A
authors.lastname: Hasegawa
authors.forename: Atae
authors.initials: A
authors.lastname: Utsunomiya
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Maeda
authors.forename: Yoshihisa
authors.initials: Y
authors.lastname: Yamano
authors.forename: Masato
authors.initials: M
authors.lastname: Masuda
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Shimizu
authors.forename: Yotaro
authors.initials: Y
authors.lastname: Tamai
authors.forename: Amane
authors.initials: A
authors.lastname: Sasada
authors.forename: Na
authors.initials: N
authors.lastname: Zeng
authors.forename: Ilseung
authors.initials: I
authors.lastname: Choi
authors.forename: Naokuni
authors.initials: N
authors.lastname: Uike
authors.forename: Jun
authors.initials: J
authors.lastname: Okamura
authors.forename: Toshiki
authors.initials: T
authors.lastname: Watanabe
authors.forename: Takao
authors.initials: T
authors.lastname: Masuda
authors.forename: Mari
authors.initials: M
authors.lastname: Kannagi
mesh_terms: D015703:Antigens, CD / Q000378:metabolism; D000945:Antigens, Differentiation, T-Lymphocyte / Q000378:metabolism; D058345:Asymptomatic Infections; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000821:virology; D049109:Cell Proliferation; D002478:Cells, Cultured; D003587:Cytomegalovirus / Q000276:immunology*; D016356:Gene Products, tax / Q000276:immunology*; D015490:HTLV-I Infections / Q000276:immunology; D015368:Human T-lymphotropic virus 1 / Q000276:immunology*; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D037181:Lectins, C-Type / Q000378:metabolism; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000276:immunology; D008213:Lymphocyte Activation; D052118:Lysosomal-Associated Membrane Protein 1 / Q000378:metabolism; D015493:Paraparesis, Tropical Spastic / Q000276:immunology / Q000821:virology; D010750:Phosphoproteins / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D014763:Viral Matrix Proteins / Q000276:immunology; D000099192:CD69 Antigens
chemical_list: D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D016356:Gene Products, tax; D007371:Interferon-gamma; D037181:Lectins, C-Type; D052118:Lysosomal-Associated Membrane Protein 1; D010750:Phosphoproteins; D014763:Viral Matrix Proteins; D000099192:CD69 Antigens; C065418:cytomegalovirus matrix protein 65kDa