Selective impairment of CD4+CD25+Foxp3+ regulatory T cells by paclitaxel is explained by Bcl-2/Bax mediated apoptosis

Nan Liu; Yijie Zheng; Ying Zhu; Shudao Xiong; Yiwei Chu

doi:10.1016/j.intimp.2010.11.021

Selective impairment of CD4+CD25+Foxp3+ regulatory T cells by paclitaxel is explained by Bcl-2/Bax mediated apoptosis

Int Immunopharmacol. 2011 Feb;11(2):212-9. doi: 10.1016/j.intimp.2010.11.021. Epub 2010 Nov 27.

Authors

Nan Liu¹, Yijie Zheng, Ying Zhu, Shudao Xiong, Yiwei Chu

Affiliation

¹ Department of Immunology, Shanghai Medical College, Key Laboratory of Molecular Medicine of Ministry of Education, Fudan University, Shanghai, People's Republic of China.

PMID: 21115120
DOI: 10.1016/j.intimp.2010.11.021

Abstract

Paclitaxel has become one of the most effective and widely used chemotherapeutic agents over the past decades. Although it has shown promise to selectively deplete regulatory T (Treg) cells in our previous study, the underlying molecular mechanism remains to be further elucidated. The present study focused on the effect of paclitaxel on Treg cells in 3LL Lewis tumor model and explored the possible molecular pathways involved in this process. We found that paclitaxel significantly decreased the percentage of Treg cells in CD4(+) cells and impaired their suppressive functions, but effector T (Teff) cells remained unaffected. Compared with Teff cells, Treg cells exhibited a high sensitivity to paclitaxel-mediated apoptosis in vitro. Interestingly, though paclitaxel has been characterized as a mitotic inhibitor, tubulin was not involved in the selective function of paclitaxel. Treg cells exposed to paclitaxel displayed downregulation of Bcl-2 and upregulation of Bax. Blocking the Bcl-2 pathway eliminated the difference between Treg and Teff cells responding to paclitaxel. These results suggest that Bcl-2 rather than tubulin contributes to the distinctive effect of paclitaxel on Treg cells. Therefore, we here identify a molecular pathway through which paclitaxel selectively ablates Treg cells.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antineoplastic Agents, Phytogenic / administration & dosage
Antineoplastic Agents, Phytogenic / pharmacology*
Antineoplastic Agents, Phytogenic / therapeutic use
Apoptosis / drug effects*
Apoptosis / immunology
Blotting, Western
CD4 Antigens / biosynthesis
CD4 Antigens / immunology*
CD4 Lymphocyte Count
Cell Culture Techniques
Cell Line, Tumor
Enzyme-Linked Immunosorbent Assay
Female
Fluorescent Antibody Technique
Forkhead Transcription Factors / biosynthesis
Forkhead Transcription Factors / immunology*
Interleukin-2 Receptor alpha Subunit / biosynthesis
Interleukin-2 Receptor alpha Subunit / immunology*
Mice
Mice, Inbred C57BL
Microscopy, Confocal
Neoplasm Transplantation
Neoplasms / drug therapy
Neoplasms / immunology
Neoplasms / metabolism
Neoplasms / pathology
Paclitaxel / administration & dosage
Paclitaxel / pharmacology*
Paclitaxel / therapeutic use
Proto-Oncogene Proteins / biosynthesis
Proto-Oncogene Proteins / physiology*
Proto-Oncogene Proteins c-bcl-2
T-Lymphocytes, Regulatory / drug effects*
T-Lymphocytes, Regulatory / immunology
bcl-2-Associated X Protein / biosynthesis
bcl-2-Associated X Protein / physiology*

Substances

Antineoplastic Agents, Phytogenic
Bax protein, mouse
CD4 Antigens
Forkhead Transcription Factors
Foxp3 protein, mouse
Interleukin-2 Receptor alpha Subunit
Proto-Oncogene Proteins
Proto-Oncogene Proteins c-bcl-2
bcl-2-Associated X Protein
Bcl2 protein, mouse
Paclitaxel