Journal of Molecular Medicine

, Volume 92, Issue 5, pp 539–550 | Cite as

Human hepatocellular carcinoma-infiltrating CD4+CD69+Foxp3 regulatory T cell suppresses T cell response via membrane-bound TGF-β1

  • Yanmei Han
  • Yuan Yang
  • Zhubo Chen
  • Zhengping Jiang
  • Yan Gu
  • Yanfang Liu
  • Sheng Xu
  • Chuan Lin
  • Zeya Pan
  • Weiping ZhouEmail author
  • Xuetao CaoEmail author
Original Article


Tumors can recruit, induce, and expand regulatory T cells (Tregs) to suppress antitumor immune responses for survival and progression. The complicated tumor-related Treg subsets and their functional mechanisms are not fully addressed yet. We have previously identified a novel CD4+CD69+CD25Foxp3 Treg subset in tumor-bearing mice, which suppresses CD4 T cell response via membrane-bound transforming growth factor beta 1 (mTGF-β1) and then promotes tumor progression. In hepatocellular carcinoma patients, here, we identified tumor-infiltrating human CD4+CD69+ Tregs which represent ~67.2 % of tumor-infiltrating CD4 T cells that is significantly higher than conventional CD4+CD25+Foxp3+ Tregs. They expressed mTGF-β1, PD-1, and CTLA-4, but not CD25 or Foxp3, and only produced a little interleukin (IL)-10 and TGF-β1. More importantly, they significantly suppressed CD4 T cell response via mTGF-β1 in vitro. Furthermore, the percentage of these CD4+CD69+ Tregs in tumor tissue was significantly correlated with tumor progression, which is more pronounced at the late stage of cancer patients. Thus, we have identified a tumor-induced new population of human CD4+CD69+ Tregs in cancer patients with phenotype of CD25Foxp3mTGF-β1+CTLA-4+PD-1+, and these Tregs can suppress antitumor immune response via mTGF-β1. Our results not only enrich the family of Treg subsets, providing new mechanistic insight to tumor-induced immune suppression in human, but also suggest a potential target for cancer immunotherapy.

Key message

  • CD4+CD69+Foxp3 regulatory T cells were identified in hepatocellular carcinoma patients.

  • These Treg cells inhibit T cell response via membrane-bound TGF-β.

  • The percentage of these cells was significantly correlated with tumor progression.

  • The percentage of these cells was higher than conventional CD4+CD25+Foxp3+ Tregs.

  • These Treg cells not only exist in tumor-bearing mice, but also in cancer patients.


Regulatory T cells CD69 Transforming growth factor-β1 Tumor immune escape Hepatocellular carcinoma 



Regulatory T cell


Membrane-bound transforming growth factor-β


Hepatocellular carcinoma


Mature dendritic cell


Cytotoxic T-lymphocyte-associated antigen 4



This work was supported by grants from the National Key Basic Research Program of China (2011CB965202, 2013CB530503), the National Natural Science Foundation of China (31170843, 81230074, 31390431), and the National 125 Major Project of China (2012ZX10002014-001, 2012ZX10002010).

Conflict of interest

The authors have no financial conflicts of interest.


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Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Yanmei Han
    • 1
  • Yuan Yang
    • 2
  • Zhubo Chen
    • 1
  • Zhengping Jiang
    • 1
  • Yan Gu
    • 1
  • Yanfang Liu
    • 1
  • Sheng Xu
    • 1
  • Chuan Lin
    • 2
  • Zeya Pan
    • 2
  • Weiping Zhou
    • 2
    Email author
  • Xuetao Cao
    • 1
    • 3
    Email author
  1. 1.National Key Laboratory of Medical Immunology & Institute of ImmunologySecond Military Medical UniversityShanghaiChina
  2. 2.Third Department of Hepatic SurgeryEastern Hepatobiliary Surgery HospitalShanghaiChina
  3. 3.National Key Laboratory of Medical Molecular Biology & Department of ImmunologyChinese Academy of Medical SciencesBeijingChina

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