title: Increased CD4(+) CD69(+) CD25(-)  T cells in patients with hepatocellular carcinoma are associated with tumor progression.
abstract: OBJECTIVE
  A new subset of Treg cells, CD4(+) CD69(+) CD25(-) T cells, has been identified in mice. Herein, we aimed to identify this subset of T cells and to evaluate its function in patients with hepatocellular carcinoma (HCC).
  
  
  METHODS
  We detected CD4(+) CD69(+) CD25(-) T cells and its expression of CCR6 and transforming growth factor-β1 (TGF-β1) in peripheral blood of 91 HCC patients, 38 chronic hepatitis patients and 34 healthy donors by flow cytometry. CD4(+) CD69(+) CD25(-) T cells in HCC tissues were also analyzed.
  
  
  RESULTS
  CD4(+) CD69(+) CD25(-) T cells were significantly increased in peripheral blood of HCC patients compared with healthy persons and chronic hepatitis patients (8.74% ± 0.42% vs 4.55% ± 0.33% and 5.15% ± 0.36%, P < 0.0001). The percentage of peripheral CD4(+) CD69(+) CD25(-) T cells was significantly higher in HCC patients with Tumor Node Metastasis (TNM) stage III plus IV (P < 0.05). Patients with large tumor size and tumor vascular invasion were inclined to obtain high percentage of CD4(+) CD69(+) CD25(-) T cells (P < 0.05). The frequency of membrane-bound TGF-β1 positive cells in CD4(+) CD69(+) CD25(-) T cells from HCC patients was higher than that from the other two groups (P < 0.0001). A considerable proportion of CD4(+) CD69(+) CD25(-) T cells were present in HCC tissues, which has significant correlation with tumor size and TNM stage. Few CD4(+) CD69(+) CD25(-) T cells express CCR6 both in peripheral blood and tumor tissues from HCC patients.
  
  
  CONCLUSIONS
  Increased CD4(+) CD69(+) CD25(-) T cells in HCC patients are significantly correlated with tumor size, vascular invasion and TNM stage. Thus, increased CD4(+) CD69(+) CD25(-) T cells exert a critical role in HCC progression and might be a clinically aggressive phenotype of HCC.
authors.affiliation: Department of General Surgery, Qilu Hospital, Shandong University, Jinan, Shandong, China.
authors.forename: Jiankang
authors.initials: J
authors.lastname: Zhu
authors.forename: Alei
authors.initials: A
authors.lastname: Feng
authors.forename: Jintang
authors.initials: J
authors.lastname: Sun
authors.forename: Zhenzhong
authors.initials: Z
authors.lastname: Jiang
authors.forename: Guangyong
authors.initials: G
authors.lastname: Zhang
authors.forename: Kexin
authors.initials: K
authors.lastname: Wang
authors.forename: Sanyuan
authors.initials: S
authors.lastname: Hu
authors.forename: Xun
authors.initials: X
authors.lastname: Qu
mesh_terms: D015703:Antigens, CD / Q000032:analysis*; D000945:Antigens, Differentiation, T-Lymphocyte / Q000032:analysis*; D018791:CD4 Lymphocyte Count; D006528:Carcinoma, Hepatocellular / Q000276:immunology* / Q000556:secondary; D016009:Chi-Square Distribution; D002681:China; D018450:Disease Progression; D005434:Flow Cytometry; D006801:Humans; D053645:Interleukin-2 Receptor alpha Subunit / Q000032:analysis*; D037181:Lectins, C-Type / Q000032:analysis*; D016014:Linear Models; D008113:Liver Neoplasms / Q000276:immunology* / Q000473:pathology; D008207:Lymphatic Metastasis; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology*; D009361:Neoplasm Invasiveness; D009367:Neoplasm Staging; D010641:Phenotype; D054399:Receptors, CCR6 / Q000032:analysis; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D053773:Transforming Growth Factor beta1 / Q000032:analysis; D047368:Tumor Burden; D000099192:CD69 Antigens
chemical_list: D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D053645:Interleukin-2 Receptor alpha Subunit; D037181:Lectins, C-Type; D054399:Receptors, CCR6; D053773:Transforming Growth Factor beta1; D000099192:CD69 Antigens; C106311:CCR6 protein, human; C508017:IL2RA protein, human; C508960:TGFB1 protein, human