Tuftsin-derived T-peptide prevents cellular immunosuppression and improves survival rate in septic mice

Yu-Lei Gao,Yong-Ming Yao,Yan-Fen Chai,Ning Dong,Qing-Hong Zhang,Xiao-Mei Zhu,Su Han

doi:10.1038/srep16725

Abstract

The primary mechanisms of sepsis induced cellular immunesuppression involve immune dysfunction of T lymphocytes and negative immunoregulation of regulatory T cells (Tregs). It has been found that tuftsin is an immune modulating peptide derived from IgG in spleen. T-peptide is one of tuftsin analogs. Herein, we examined the effect of T-peptide on cell-mediated immunity in the presence of lipopolysaccharide (LPS) and the survival rate in septic mice. T-peptide regulated the proliferative ability of CD4+CD25− T cells in dual responses. Meanwhile, 10 and 100 μg/ml T-peptides were able to enhance the apoptotic rate of CD4+CD25− T cells compared with 1 μg/ml T-peptide, but markedly lowered interleukin (IL)-2 levels. When CD4+CD25+ Tregs were treated with T-peptide for 24 hours, and co-cultured with normal CD4+CD25− T cells, the suppressive ability of CD4+CD25+ Tregs on CD4+CD25− T cells was significantly lowered, along with decreased expression in forkhead/winged helix transcription factor p-3 (Foxp-3) as well as cytotoxic T lymphocyte-associated antigen (CTLA)-4, and secretion of transforming growth factor (TGF)-β. Moreover, T-peptide has the ability to improve outcome of septic mice in a dose- and time- dependent manner, and associated with improvement in the microenvironment of cellular immunosuppression in septic mice.

Highlights

We first reported that tuftsin-derived T-peptide had a marked therapeutic effect on improvement of the outcome of severe sepsis in a dose- and time-dependent manner via regulating host immune response, especially T cell-mediated immunity
Immediate observation of specimens of spleen, thymus, and lung in septic patients who died in intensive care units or murine CLP model showed a profound, progressive, apoptosis-induced loss of adaptive immunocytes, thereby resulting in a decrease in ability of producing antibodies and clearing life-threatening pathogens[7,10,11,15,17,18,19]
A shift to Th2 response was corroborated in sepsis-induced immune suppression, and the secretion of Th1 associated cytokines was thereby impaired, and on the other hand the secretion of Th2 associated cytokines was increased during sepsis, and this phenomenon was obviously correlated with the outcome of septic complications[11,24]

Summary

Introduction

Tuftsin or tuftsin-like peptides were found to exert therapeutic effect to improve outcome and their innate immunity. T-peptide is one of tuftsin analogs, and it is characterized by its stable structure and long half life compared with tuftsin. It had been demonstrated that tuftsin-derived T-peptide was a potential postoperative adjuvant in cancer therapy, and it showed an inhibitory effect on growth of residual tumor cells after surgical resection[42]. The objective was to investigate the effect of tuftsin-derived T-peptide on cell-mediated immunity after LPS stimulation and the survival rate in septic mice

Methods

Results

Conclusion