title: Comparative analyses of regulatory T cell subsets in patients with hepatocellular carcinoma: a crucial role of CD25(-) FOXP3(-) T cells.
abstract: Regulatory T cells (Tregs) play pivotal role in cancer-induced immunoediting. Increment of CD25(high+) FOXP3+ natural Tregs has been reported in patients with hepatocellular carcinoma (HCC); however, the involvement of other type of Tregs remain elusive. We aimed to clarify whether FOXP3- Tregs are increased and functionally suppressive or not in patients with HCC. We enrolled 184 hepatitis C-infected patients with chronic liver diseases or HCC, 57 healthy subjects and 27 HCC patients with other etiology. Distinct Treg subsets were phenotypically identified by the expression of CD4, CD25, CD127 and forkhead/winged helix transcription factor (FOXP3). Their gene profiles, frequency and suppressor functions against T cell proliferation were compared among the subjects. To examine the molecules involving in Treg differentiation, we cultured naive CD4+ T cells in the presence of HCC cells and dendritic cells. We determined two types of CD4+ CD127- T cells with comparable regulatory ability; one is CD25(high+) cells expressing FOXP3 (CD25(high+) FOXP3+ Tregs) and the other is CD25- cells without FOXP3- expression (CD25- FOXP3- cells). The peripheral or intrahepatic frequency of CD25- FOXP3- Tregs in HCC patients is higher than those in other groups, of which significance is more than CD25(high+) FOXP3+ cells. Of importance, CD25- FOXP3- Tregs, but not CD25(high+) FOXP3+ cells, dynamically change in patients accompanied by the ablation or the recurrence of HCC. CD25- FOXP3- T cells with CD127- IL-10+ phenoype are inducible in vitro from naive CD4(+) T cells, in which programmed cell death 1 ligand 1, immunoglobulin-like transcript 4 and human leukocyte antigen G are involved.. In conclusion, CD25- FOXP3- Tregs with suppressive capacity are increased in patients with HCC, suggesting their distinct roles from CD25+ FOXP3+ Tregs.
authors.affiliation: Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan.
authors.forename: Naruyasu
authors.initials: N
authors.lastname: Kakita
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Kanto
authors.forename: Ichiyo
authors.initials: I
authors.lastname: Itose
authors.forename: Shoko
authors.initials: S
authors.lastname: Kuroda
authors.forename: Michiyo
authors.initials: M
authors.lastname: Inoue
authors.forename: Tokuhiro
authors.initials: T
authors.lastname: Matsubara
authors.forename: Koyo
authors.initials: K
authors.lastname: Higashitani
authors.forename: Masanori
authors.initials: M
authors.lastname: Miyazaki
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Sakakibara
authors.forename: Naoki
authors.initials: N
authors.lastname: Hiramatsu
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Takehara
authors.forename: Akinori
authors.initials: A
authors.lastname: Kasahara
authors.forename: Norio
authors.initials: N
authors.lastname: Hayashi
mesh_terms: D000368:Aged; D060890:B7-H1 Antigen / Q000235:genetics / Q000276:immunology; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000276:immunology*; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D048708:Cell Growth Processes / Q000235:genetics / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology; D018450:Disease Progression; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000276:immunology*; D006680:HLA Antigens / Q000235:genetics / Q000276:immunology; D006526:Hepatitis C / Q000276:immunology; D006801:Humans; D016753:Interleukin-10 / Q000235:genetics / Q000276:immunology; D053645:Interleukin-2 Receptor alpha Subunit / Q000235:genetics / Q000276:immunology*; D053699:Interleukin-7 Receptor alpha Subunit / Q000235:genetics / Q000276:immunology; D008113:Liver Neoplasms / Q000235:genetics / Q000276:immunology*; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics / Q000276:immunology; D008875:Middle Aged; D011971:Receptors, Immunologic / Q000235:genetics / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
chemical_list: D060890:B7-H1 Antigen; C423236:CD274 protein, human; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D006680:HLA Antigens; C508017:IL2RA protein, human; D053645:Interleukin-2 Receptor alpha Subunit; D053699:Interleukin-7 Receptor alpha Subunit; C491341:LILRB2 protein, human; D008562:Membrane Glycoproteins; D011971:Receptors, Immunologic; D016753:Interleukin-10