A Trichosanthin-derived peptide suppresses type 1 immune responses by TLR2-dependent activation of CD8(+)CD28(-) Tregs

Neng Yang; Zuoqing Li; Zhijun Jiao; Peng Gu; Yun Zhou; Liming Lu; Kuang-Yen Chou

doi:10.1016/j.clim.2014.05.005

A Trichosanthin-derived peptide suppresses type 1 immune responses by TLR2-dependent activation of CD8(+)CD28(-) Tregs

Clin Immunol. 2014 Aug;153(2):277-87. doi: 10.1016/j.clim.2014.05.005. Epub 2014 May 22.

Authors

Neng Yang¹, Zuoqing Li², Zhijun Jiao², Peng Gu¹, Yun Zhou², Liming Lu³, Kuang-Yen Chou⁴

Affiliations

¹ Department of Immunology, Shanghai Jiaotong University School of Medicine, China.
² Shanghai Institute of Immunology, Shanghai 200025, China.
³ Shanghai Institute of Immunology, Shanghai 200025, China. Electronic address: [email protected].
⁴ Department of Immunology, Shanghai Jiaotong University School of Medicine, China. Electronic address: [email protected].

PMID: 24858261
DOI: 10.1016/j.clim.2014.05.005

Abstract

A group of 15-aa-long Trichosanthin-derived peptides was synthesized and screened based on their differential abilities to induce low-responsiveness in mouse strains with high and low susceptibility. One of them was conjugated to form a homo-tetramer Tk-tPN. At concentrations of 0.1-50 μg/ml, Tk-tPN activated CD8(+)CD28(-) Tregs in vitro to induce immune suppression as effectively as the native Trichosanthin but did not exhibit cytotoxicity. In EAE mice which were pre-treated with Tk-tPN or Tk-tPN-activated CD8(+) T cells, a marked attenuation of clinical scores was recorded together with an expansion of the CD8(+)CD28(-) Treg from 2.2% to 36.1% in vivo. A pull-down assay and signal transduction analyses indicated that the ability of Tk-tPN to convert the CD8(+)CD28(-) Treg-related cytokine secretion pattern from type 1 to type 2 depends on the TLR2-initiated signaling in macrophages. The high production of IL-4/IL-10 by the Tk-tPN-activated CD8(+)CD28(-) Treg suggests the value of using Tk-tPN as a therapeutic reagent for Th1-dominant immunological diseases.

Keywords: CD8(+)CD28(−) Treg; EAE; TLR2 signaling; Trichosanthin-derived peptide.

Publication types

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

MeSH terms

Animals
CD28 Antigens / immunology
CD28 Antigens / metabolism
CD8 Antigens / immunology
CD8 Antigens / metabolism
Cell Line
Cell Survival / drug effects
Cell Survival / genetics
Cell Survival / immunology
Encephalomyelitis, Autoimmune, Experimental / immunology
Encephalomyelitis, Autoimmune, Experimental / metabolism
Encephalomyelitis, Autoimmune, Experimental / prevention & control
Flow Cytometry
Interleukin-10 / immunology
Interleukin-10 / metabolism
Interleukin-4 / immunology
Interleukin-4 / metabolism
Lymphocyte Activation / drug effects
Lymphocyte Activation / immunology*
Macrophages / drug effects
Macrophages / immunology
Macrophages / metabolism
Male
Mice
Mice, Inbred BALB C
Mice, Inbred C3H
Mice, Inbred C57BL
Mice, Knockout
Peptides / immunology*
Peptides / pharmacology
Signal Transduction / drug effects
Signal Transduction / genetics
Signal Transduction / immunology
T-Lymphocytes, Regulatory / drug effects
T-Lymphocytes, Regulatory / immunology*
T-Lymphocytes, Regulatory / metabolism
Th1 Cells / drug effects
Th1 Cells / immunology*
Th1 Cells / metabolism
Th2 Cells / drug effects
Th2 Cells / immunology
Th2 Cells / metabolism
Toll-Like Receptor 2 / deficiency
Toll-Like Receptor 2 / genetics
Toll-Like Receptor 2 / immunology*
Trichosanthin / chemistry
Trichosanthin / immunology*
Trichosanthin / pharmacology

Substances

CD28 Antigens
CD8 Antigens
Peptides
Tlr2 protein, mouse
Toll-Like Receptor 2
Interleukin-10
Interleukin-4
Trichosanthin