title: Augmented expression of programmed death-1 in both neoplastic and non-neoplastic CD4+ T-cells in adult T-cell leukemia/lymphoma.
abstract: Adult T-cell leukemia/lymphoma (ATL) is a CD4(+)CD25(+) T-cell malignancy infected with human T-cell leukemia virus type-I (HTLV-I). HTLV-I infection causes the T-cell dysfunction, which contributes to the immunodeficient state of the patients. Programmed death-1 (PD-1) can negatively regulate T-cell response, when its ligand, PD-L1 or PD-L2 mainly expressed on antigen presenting cells, binds to this B7 family receptor. We investigated whether PD-1 is expressed on CD4(+) neoplastic (and/or non-neoplastic) cells or CD8(+) cytotoxic cells in peripheral blood mononuclear cells from 11 patients with ATL. By flow cytometry, we found that the levels of PD-1 expression on both CD4(+)CD25(+) and CD4(+)CD25(-) T-cell populations were increased in ATL patients compared to normal healthy volunteers, while PD-1 levels on CD8(+) T-cells were comparable between the patients and normal subjects. In stimulation with anti-CD3 antibody, the proliferation of PD-1-expressing T-cells from ATL patients was weak when compared to that of PD-1-nonexpressing normal T-cells. In addition to PD-1, PD-L1 was coexpressed on ATL cells in some patients, and PD-L1 expression was enhanced by stimulation with anti-CD3 antibody. Finally, the production of cytokines such as TNF-alpha by ATL cells was restored by blockade of PD-1/PD-L1 interaction. These findings suggest that CD4(+) T-cells are the main PD-1-expressing cells rather than CD8(+) T-cells in ATL patients, and both neoplastic and normal CD4(+) cells are exhausted as a result of PD-1 expression, and additionally PD-L1 expression on the neoplastic cell.
authors.affiliation: Department of Dermatology, University of Occupational and Environmental Health, Japan, Kitakyusyu, Fukuoka, Japan. t-shima@med.uoeh-u.ac.jp
authors.forename: Takatoshi
authors.initials: T
authors.lastname: Shimauchi
authors.forename: Kenji
authors.initials: K
authors.lastname: Kabashima
authors.forename: Daiki
authors.initials: D
authors.lastname: Nakashima
authors.forename: Kazunari
authors.initials: K
authors.lastname: Sugita
authors.forename: Yoko
authors.initials: Y
authors.lastname: Yamada
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Hino
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Tokura
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D015703:Antigens, CD / Q000378:metabolism*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism*; D016022:Case-Control Studies; D049109:Cell Proliferation; D005260:Female; D005434:Flow Cytometry; D005786:Gene Expression Regulation; D015973:Gene Expression Regulation, Leukemic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism; D007564:Japan; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000378:metabolism*; D008213:Lymphocyte Activation; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000378:metabolism; D061026:Programmed Cell Death 1 Receptor; D015854:Up-Regulation
chemical_list: D015703:Antigens, CD; D051017:Apoptosis Regulatory Proteins; D053645:Interleukin-2 Receptor alpha Subunit; D009363:Neoplasm Proteins; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor