TRAIL-mediated suppression of T cell receptor signaling inhibits T cell activation and inflammation in experimental autoimmune encephalomyelitis

I. Tsu Chyuan, Hwei Fang Tsai, Chien Sheng Wu, Chi Chang Sung, Ping Ning Hsu

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

Objective: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces cell apoptosis by transducing apoptosis signals after interacting with its receptor (TRAIL-R). Although the actual biological role of TRAIL remains to be elucidated, recent accumulating evidence implies that TRAIL regulates immune responses and immune cell homeostasis via an apoptosis-independent pathway, suggesting a novel immune-regulatory role of TRAIL in autoimmune diseases. The purpose of this study is to address the immune-regulatory role and molecular mechanism of TRAIL in regulating T cell activation in autoimmune diseases. Design: TRAIL was administered to mice to induce experimental autoimmune encephalomyelitis (EAE), and to evaluate its impact on neuroinflammation and disease activity. The effects of TRAIL on neuroantigen [myelin oligodendrocyte glycoprotein (MOG)35-55]-activated T cell proliferation and cytokine production were investigated. TRAIL-treated MOG35-55-activated splenic Th17 cells were further adoptively transferred into Rag1 KO mice to induce passive EAE. Gene expression profiles of CD4+ T cells from EAE mice treated with TRAIL were analyzed by RNA sequencing and transcriptome analysis. Results: TRAIL suppressed autoimmune encephalomyelitis and inhibited T cell reactivity to neuro-antigen in murine EAE, and the effects were dependent on TRAIL-R signaling. Moreover, TRAIL directly inhibited activation of MOG35-55-activated CD4+ T cells, resulting in suppression of neuroinflammation and reduced disease activity in adoptive transfer-induced EAE. Furthermore, TRAIL-R signaling inhibited phosphorylation of proximal T cell receptor (TCR)-associated tyrosine kinases in activated CD4+ T cells. Importantly, TRAIL/TRAIL-R interaction downregulated TCR downstream signaling genes in RNA sequencing and transcriptome analysis. Conclusion: TRAIL/TRAIL-R interaction regulates CD4+ T cell activation in autoimmune inflammation and directly suppresses T cell activation via inhibiting TCR signaling, suggesting that TRAIL-R serves as a novel immune checkpoint in T cell responses.

Original languageEnglish
Article number15
JournalFrontiers in Immunology
Volume9
Issue numberJAN
DOIs
Publication statusPublished - Jan 22 2018

Fingerprint

Autoimmune Experimental Encephalomyelitis
T-Cell Antigen Receptor
Inflammation
T-Lymphocytes
Apoptosis
RNA Sequence Analysis
Gene Expression Profiling
Autoimmune Diseases
TNF-Related Apoptosis-Inducing Ligand Receptors
Encephalomyelitis
Th17 Cells
Adoptive Transfer
Transcriptome
Protein-Tyrosine Kinases
Homeostasis
Down-Regulation
Tumor Necrosis Factor-alpha
Phosphorylation
Cell Proliferation
Cytokines

Keywords

  • Apoptosis
  • Experimental autoimmune encephalomyelitis
  • T cell activation
  • T cell receptor signaling
  • TRAIL

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

TRAIL-mediated suppression of T cell receptor signaling inhibits T cell activation and inflammation in experimental autoimmune encephalomyelitis. / Chyuan, I. Tsu; Tsai, Hwei Fang; Wu, Chien Sheng; Sung, Chi Chang; Hsu, Ping Ning.

In: Frontiers in Immunology, Vol. 9, No. JAN, 15, 22.01.2018.

Research output: Contribution to journalArticle

@article{3ff77bbab0d14d148e740b66a7e27f44,
title = "TRAIL-mediated suppression of T cell receptor signaling inhibits T cell activation and inflammation in experimental autoimmune encephalomyelitis",
abstract = "Objective: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces cell apoptosis by transducing apoptosis signals after interacting with its receptor (TRAIL-R). Although the actual biological role of TRAIL remains to be elucidated, recent accumulating evidence implies that TRAIL regulates immune responses and immune cell homeostasis via an apoptosis-independent pathway, suggesting a novel immune-regulatory role of TRAIL in autoimmune diseases. The purpose of this study is to address the immune-regulatory role and molecular mechanism of TRAIL in regulating T cell activation in autoimmune diseases. Design: TRAIL was administered to mice to induce experimental autoimmune encephalomyelitis (EAE), and to evaluate its impact on neuroinflammation and disease activity. The effects of TRAIL on neuroantigen [myelin oligodendrocyte glycoprotein (MOG)35-55]-activated T cell proliferation and cytokine production were investigated. TRAIL-treated MOG35-55-activated splenic Th17 cells were further adoptively transferred into Rag1 KO mice to induce passive EAE. Gene expression profiles of CD4+ T cells from EAE mice treated with TRAIL were analyzed by RNA sequencing and transcriptome analysis. Results: TRAIL suppressed autoimmune encephalomyelitis and inhibited T cell reactivity to neuro-antigen in murine EAE, and the effects were dependent on TRAIL-R signaling. Moreover, TRAIL directly inhibited activation of MOG35-55-activated CD4+ T cells, resulting in suppression of neuroinflammation and reduced disease activity in adoptive transfer-induced EAE. Furthermore, TRAIL-R signaling inhibited phosphorylation of proximal T cell receptor (TCR)-associated tyrosine kinases in activated CD4+ T cells. Importantly, TRAIL/TRAIL-R interaction downregulated TCR downstream signaling genes in RNA sequencing and transcriptome analysis. Conclusion: TRAIL/TRAIL-R interaction regulates CD4+ T cell activation in autoimmune inflammation and directly suppresses T cell activation via inhibiting TCR signaling, suggesting that TRAIL-R serves as a novel immune checkpoint in T cell responses.",
keywords = "Apoptosis, Experimental autoimmune encephalomyelitis, T cell activation, T cell receptor signaling, TRAIL",
author = "Chyuan, {I. Tsu} and Tsai, {Hwei Fang} and Wu, {Chien Sheng} and Sung, {Chi Chang} and Hsu, {Ping Ning}",
year = "2018",
month = "1",
day = "22",
doi = "10.3389/fimmu.2018.00015",
language = "English",
volume = "9",
journal = "Frontiers in Immunology",
issn = "1664-3224",
publisher = "Frontiers Media S. A.",
number = "JAN",

}

TY - JOUR

T1 - TRAIL-mediated suppression of T cell receptor signaling inhibits T cell activation and inflammation in experimental autoimmune encephalomyelitis

AU - Chyuan, I. Tsu

AU - Tsai, Hwei Fang

AU - Wu, Chien Sheng

AU - Sung, Chi Chang

AU - Hsu, Ping Ning

PY - 2018/1/22

Y1 - 2018/1/22

N2 - Objective: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces cell apoptosis by transducing apoptosis signals after interacting with its receptor (TRAIL-R). Although the actual biological role of TRAIL remains to be elucidated, recent accumulating evidence implies that TRAIL regulates immune responses and immune cell homeostasis via an apoptosis-independent pathway, suggesting a novel immune-regulatory role of TRAIL in autoimmune diseases. The purpose of this study is to address the immune-regulatory role and molecular mechanism of TRAIL in regulating T cell activation in autoimmune diseases. Design: TRAIL was administered to mice to induce experimental autoimmune encephalomyelitis (EAE), and to evaluate its impact on neuroinflammation and disease activity. The effects of TRAIL on neuroantigen [myelin oligodendrocyte glycoprotein (MOG)35-55]-activated T cell proliferation and cytokine production were investigated. TRAIL-treated MOG35-55-activated splenic Th17 cells were further adoptively transferred into Rag1 KO mice to induce passive EAE. Gene expression profiles of CD4+ T cells from EAE mice treated with TRAIL were analyzed by RNA sequencing and transcriptome analysis. Results: TRAIL suppressed autoimmune encephalomyelitis and inhibited T cell reactivity to neuro-antigen in murine EAE, and the effects were dependent on TRAIL-R signaling. Moreover, TRAIL directly inhibited activation of MOG35-55-activated CD4+ T cells, resulting in suppression of neuroinflammation and reduced disease activity in adoptive transfer-induced EAE. Furthermore, TRAIL-R signaling inhibited phosphorylation of proximal T cell receptor (TCR)-associated tyrosine kinases in activated CD4+ T cells. Importantly, TRAIL/TRAIL-R interaction downregulated TCR downstream signaling genes in RNA sequencing and transcriptome analysis. Conclusion: TRAIL/TRAIL-R interaction regulates CD4+ T cell activation in autoimmune inflammation and directly suppresses T cell activation via inhibiting TCR signaling, suggesting that TRAIL-R serves as a novel immune checkpoint in T cell responses.

AB - Objective: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces cell apoptosis by transducing apoptosis signals after interacting with its receptor (TRAIL-R). Although the actual biological role of TRAIL remains to be elucidated, recent accumulating evidence implies that TRAIL regulates immune responses and immune cell homeostasis via an apoptosis-independent pathway, suggesting a novel immune-regulatory role of TRAIL in autoimmune diseases. The purpose of this study is to address the immune-regulatory role and molecular mechanism of TRAIL in regulating T cell activation in autoimmune diseases. Design: TRAIL was administered to mice to induce experimental autoimmune encephalomyelitis (EAE), and to evaluate its impact on neuroinflammation and disease activity. The effects of TRAIL on neuroantigen [myelin oligodendrocyte glycoprotein (MOG)35-55]-activated T cell proliferation and cytokine production were investigated. TRAIL-treated MOG35-55-activated splenic Th17 cells were further adoptively transferred into Rag1 KO mice to induce passive EAE. Gene expression profiles of CD4+ T cells from EAE mice treated with TRAIL were analyzed by RNA sequencing and transcriptome analysis. Results: TRAIL suppressed autoimmune encephalomyelitis and inhibited T cell reactivity to neuro-antigen in murine EAE, and the effects were dependent on TRAIL-R signaling. Moreover, TRAIL directly inhibited activation of MOG35-55-activated CD4+ T cells, resulting in suppression of neuroinflammation and reduced disease activity in adoptive transfer-induced EAE. Furthermore, TRAIL-R signaling inhibited phosphorylation of proximal T cell receptor (TCR)-associated tyrosine kinases in activated CD4+ T cells. Importantly, TRAIL/TRAIL-R interaction downregulated TCR downstream signaling genes in RNA sequencing and transcriptome analysis. Conclusion: TRAIL/TRAIL-R interaction regulates CD4+ T cell activation in autoimmune inflammation and directly suppresses T cell activation via inhibiting TCR signaling, suggesting that TRAIL-R serves as a novel immune checkpoint in T cell responses.

KW - Apoptosis

KW - Experimental autoimmune encephalomyelitis

KW - T cell activation

KW - T cell receptor signaling

KW - TRAIL

UR - http://www.scopus.com/inward/record.url?scp=85040987471&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85040987471&partnerID=8YFLogxK

U2 - 10.3389/fimmu.2018.00015

DO - 10.3389/fimmu.2018.00015

M3 - Article

VL - 9

JO - Frontiers in Immunology

JF - Frontiers in Immunology

SN - 1664-3224

IS - JAN

M1 - 15

ER -