Selective impairment of CD4+CD25+Foxp3+ regulatory T cells by paclitaxel is explained by Bcl-2/Bax mediated apoptosis.
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.
Department of Immunology, Shanghai Medical College, Key Laboratory of Molecular Medicine of Ministry of Education, Fudan University, Shanghai, People's Republic of China.
Nan
N
Liu
Yijie
Y
Zheng
Ying
Y
Zhu
Shudao
S
Xiong
Yiwei
Y
Chu
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects* / Q000276:immunology; D015153:Blotting, Western; D015704:CD4 Antigens / Q000096:biosynthesis / Q000276:immunology*; D018791:CD4 Lymphocyte Count; D018929:Cell Culture Techniques; D045744:Cell Line, Tumor; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005455:Fluorescent Antibody Technique; D051858:Forkhead Transcription Factors / Q000096:biosynthesis / Q000276:immunology*; D053645:Interleukin-2 Receptor alpha Subunit / Q000096:biosynthesis / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018613:Microscopy, Confocal; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D017239:Paclitaxel / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000502:physiology*; D019253:Proto-Oncogene Proteins c-bcl-2; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects* / Q000276:immunology; D051028:bcl-2-Associated X Protein / Q000096:biosynthesis / Q000502:physiology*
D000972:Antineoplastic Agents, Phytogenic; C494827:Bax protein, mouse; D015704:CD4 Antigens; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D053645:Interleukin-2 Receptor alpha Subunit; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; C052617:Bcl2 protein, mouse; D017239:Paclitaxel