Impaired function of CD4+ T follicular helper (Tfh) cells associated with hepatocellular carcinoma progression

PLoS One. 2015 Feb 17;10(2):e0117458. doi: 10.1371/journal.pone.0117458. eCollection 2015.


Background and aims: CD4+ T follicular helper (Tfh) cells, a new subset of immune cells, have been demonstrated to be involved in the development and prognosis of tumors. However, their functional role in human hepatocellular carcinoma (HCC) is relatively unknown, and the detailed mechanisms in HCC development remain to be described.

Methods: A total of 85 HCC patients with hepatitis B virus (HBV) infection, 25 HBV-relative liver cirrhosis (LC) patients, and 20 healthy controls (HC) were randomly enrolled. Flow cytometric analysis, immunohistochemical staining, and relative function (i.e., cytokine secretion, B cell maturation) assays were used to analyze the properties of CXCR5+CD4+ T cells. In addition, the relationship between the frequency of CXCR5+CD4+ T cells and overall survival rates or disease-free survival rates was also analyzed by the Kaplan-Meier method.

Results: The frequency of circulating CXCR5+CD4+ T cells was significantly decreased in HCC patients compared with HBV-relative liver cirrhosis (LC) patients and healthy controls, and the decrease in circulating CXCR5+CD4+ T cells correlated with disease progression. The proportion of infiltrated CXCR5+CD4+ T cells was significantly decreased in tumor regions compared with nontumor regions. Furthermore, compared with healthy controls, the function of circulating CXCR5+CD4+ T cells in HCC was impaired, with reduced IL-21 secretion and dysfunction in promoting B cell maturation. Importantly, follow-up data indicated that a decreased frequency of circulating CXCR5+CD4+ T cells was also associated with reduced disease-free survival time in HCC patients.

Conclusions: Impairment of CD4+ T follicular helper cells may influence the development of HBV-associated HCC. Decreased CD4+ T follicular helper cells may represent a potential prognostic marker and serve as a novel therapeutic target for HCC patients.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • B-Lymphocytes / cytology
  • B-Lymphocytes / immunology
  • CD4 Antigens / metabolism*
  • Carcinoma, Hepatocellular / etiology
  • Carcinoma, Hepatocellular / mortality
  • Carcinoma, Hepatocellular / pathology*
  • Disease Progression
  • Disease-Free Survival
  • Female
  • Hepatitis B / complications
  • Humans
  • Interferon-gamma / metabolism
  • Interleukins / metabolism
  • Leukocytes, Mononuclear / cytology
  • Leukocytes, Mononuclear / immunology
  • Liver / cytology
  • Liver / pathology
  • Liver Cirrhosis / etiology
  • Liver Cirrhosis / pathology
  • Liver Neoplasms / etiology
  • Liver Neoplasms / mortality
  • Liver Neoplasms / pathology*
  • Male
  • Middle Aged
  • Receptors, CXCR5 / metabolism
  • T-Lymphocytes, Helper-Inducer / cytology
  • T-Lymphocytes, Helper-Inducer / immunology*
  • T-Lymphocytes, Helper-Inducer / metabolism
  • alpha-Fetoproteins / analysis


  • CD4 Antigens
  • Interleukins
  • Receptors, CXCR5
  • alpha-Fetoproteins
  • Interferon-gamma
  • interleukin-21

Grant support

This work was supported by the National Natural Science Foundation of China (81101589), National Grand Program on Key Infectious Disease (2012ZX10001006-003-003) and Beijing Municipal & Technology Commission (Z131100004013041). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.