A Role for Trichosanthin in the Expansion of CD4⁺CD25⁺Regulatory T Cells

Abstract

CD4+CD25+ regulatory T cells (Tregs) are critical for the peripheral immune tolerance. Understanding the signals for the generation of Tregs is important for the clinical immunotherapy, but only limited progress has been made on obtaining enough peripheral Tregs. The aim of this study was to evaluate the role of trichosanthin (Tk) extracted from Chinese medicinal herb Trichosanthes kirilowi on the function of Tregs in vitro and in vivo. We reported here that Tk is needed for the expansion of freshly isolated CD4+CD25+Tregs (nTregs) into Tk‐expanded CD4+CD25+Tregs (Tk‐Tregs) through up‐regulating CD25 and Foxp3 expression. The dose–response analyses indicated that 100 ng/ml Tk was the most appropriate dose. The result of real‐time PCR showed that Tk‐Tregs expressed 1.5‐fold higher levels of Foxp3 than those observed in nTregs. Tk‐Tregs markedly suppressed activation of effector T cells at a suppressor/responder ratio of 1:1, 1:2, 1:4, 1:8 or 1:16, and their effect was dose dependent. Moreover, Tk‐Tregs secreted more immunosuppressive cytokines interleukin (IL)‐10 and transforming growth factor (TGF)‐β1 after stimulating with antigen and antigen‐presenting cells (APC). Transwell experiments showed that not only cell‐to‐cell contact but also soluble cytokines were involved in suppressive mechanism of Tk‐Tregs. And Tk‐Tregs were more efficient in suppressing CD25−T cell response to specific antigen than to irrelative antigen. Most importantly, it was revealed for the first time that Tk‐Tregs could prolong the survival duration of mice with acute graft‐versus‐host disease (aGVHD). In conclusion, the study suggests a possible therapeutic potential of Tk‐Tregs for clinical treatment on aGVHD.

Recent Progress in Medicinal Investigations on Trichosanthin and other Ribosome Inactivating Proteins from the Plant Genus Trichosanthes

“…Compared with Tregs, in vitro studies showed that TCS-Tregs caused profound inhibition of T-cell responsiveness, resulting from the production of higher levels of immune suppressor cytokines such as IL-10 and transforming growth factor-1 [82,83]. Furthermore, TCS-Tregs prolonged the survival of mice with acute graft-versushost disease [83].…”

Correlation between Th17 and nTreg cell frequencies and the stages of progression in chronic hepatitis B

“…Regulatory T (Treg) cells, a family of immunomodulatory cell types, are critical homeostatic regulators of immune and inflammatory responses. CD4 + CD25 + Tregs suppress immune responses to maintain unresponsiveness to self-antigens and prevent excessive immune responses against fatal inflammatory damage (19)(20)(21). Treg cells, which have immune incompetence and immunosuppressive characteristics, are important in CHB and chronic hepatitis C (22)(23)(24).…”

Advances on Delivery of Cytotoxic Enzymes as Anticancer Agents

“…TCS was found to enhance effector T cell and interferon γ levels. CD4+CD25+ T cells, a subtype of T lymphocytes, were demonstrated to be significantly enhanced by TCS treatment, and these TCS-enhanced cells possessed higher suppressive activity as effector T cells in vitro [35]. However, this effect was dependent on cytokine secretion and cell-cell contacts.…”