title: Programmed death-1 (PD-1)/PD-1 ligand pathway-mediated immune responses against human T-lymphotropic virus type 1 (HTLV-1) in HTLV-1-associated myelopathy/tropical spastic paraparesis and carriers with autoimmune disorders.
abstract: Human T-lymphotropic virus-1 (HTLV-1) causes HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) and adult T-cell leukemia-lymphoma in individuals with dysfunctional immune responses. In this study, to characterize the HTLV-1-specific cytotoxic T lymphocyte (CTL) populations in asymptomatic HTLV-1 carriers (ACs), HAM/TSP patients, and carriers with autoimmune disorders (CAIDs), we examined the role of programmed death-1 and its ligand (PD-1/PD-L1) in HTLV-1-specific CTL functions using an HTLV-1 Tax/HLA-A*0201 tetramer and an HTLV-1 Tax/HLA-A*2402 tetramer. Interestingly, the percentage of HTLV-1 Tax301-309/HLA-A*2402 tetramer(+)CD8(+) cells expressing PD-1 in ACs was significantly higher than the percentage of HTLV-1 Tax11-19/HLA-A*0201 tetramer(+)CD8(+) cells expressing PD-1. PD-1 expression was significantly downregulated on HTLV-1-specific CTLs in HAM/TSP compared with ACs. PD-L1 expression was observed in a small proportion of unstimulated lymphocytes from ACs and was greater in ACs than in HAM/TSP and CAIDs after short-term culture. Furthermore, CTL degranulation was impaired in HAM/TSP, whereas anti-PD-L1 blockade significantly increased CTL function in ACs. Downregulation of PD-1 on HTLV-1-specific CTLs and loss of PD-L1 expression in HAM/TSP and CAIDs, along with impaired function of HTLV-1-specific CTLs in HAM/TSP, may underlie the apparently dysfunctional immune response against HTLV-1.
authors.affiliation: Center for Chronic Viral Diseases, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan. kozako@fukuoka-u.ac.jp
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Kozako
authors.forename: Makoto
authors.initials: M
authors.lastname: Yoshimitsu
authors.forename: Masaki
authors.initials: M
authors.lastname: Akimoto
authors.forename: Yohann
authors.initials: Y
authors.lastname: White
authors.forename: Kakushi
authors.initials: K
authors.lastname: Matsushita
authors.forename: Shinji
authors.initials: S
authors.lastname: Soeda
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Shimeno
authors.forename: Ryuji
authors.initials: R
authors.lastname: Kubota
authors.forename: Shuji
authors.initials: S
authors.lastname: Izumo
authors.forename: Naomichi
authors.initials: N
authors.lastname: Arima
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019138:Antibodies, Blocking / Q000494:pharmacology; D000943:Antigens, Differentiation / Q000235:genetics / Q000378:metabolism*; D058070:Asymptomatic Diseases; D001327:Autoimmune Diseases / Q000150:complications / Q000276:immunology* / Q000503:physiopathology; D060890:B7-H1 Antigen / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D002353:Carrier State; D002478:Cells, Cultured; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D005260:Female; D005786:Gene Expression Regulation / Q000276:immunology; D015789:HLA-A2 Antigen / Q000378:metabolism; D059871:HLA-A24 Antigen / Q000378:metabolism; D015490:HTLV-I Infections / Q000150:complications / Q000276:immunology* / Q000503:physiopathology; D015368:Human T-lymphotropic virus 1 / Q000276:immunology* / Q000472:pathogenicity; D006801:Humans; D016130:Immunophenotyping; D016399:Lymphoma, T-Cell; D008297:Male; D008875:Middle Aged; D015493:Paraparesis, Tropical Spastic; D061026:Programmed Cell Death 1 Receptor; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000378:metabolism* / Q000473:pathology / Q000821:virology
chemical_list: D019138:Antibodies, Blocking; D000943:Antigens, Differentiation; D060890:B7-H1 Antigen; C423236:CD274 protein, human; C435939:HLA-A*02:01 antigen; C438506:HLA-A*24:02 antigen; D015789:HLA-A2 Antigen; D059871:HLA-A24 Antigen; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor