Abstract
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. 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. 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. 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.
Highlights
MATERIALS AND METHODSTumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a type II transmembrane protein of the TNF superfamily, expressed in a wide range of tissues, and shares high homology with Fas ligand [1,2,3,4]
To further determine whether TRAIL affects the reactivity of encephalitogenic T cells, we investigated MOG35–55-specific T cell responses in EAE mice treated with TRAIL
Numbers of IL-17- and IFN-γ-producing T cells that had infiltrated into the Central Nervous System (CNS) were greatly reduced in TRAILtreated EAE mice compared to vehicle-treated EAE mice in flow cytometric analyses (Figure 1D)
Summary
MATERIALS AND METHODSTRAIL is a type II transmembrane protein of the TNF superfamily, expressed in a wide range of tissues, and shares high homology with Fas ligand [1,2,3,4]. TRAIL induces apoptosis via binding of its death-inducing receptors [5, 6]. Only one death-inducing receptor was identified that shares high homology with human DR5/TRAIL-R2 (mouse KILLER/DR5) [4]. TRAIL administration induced anti-inflammation in several autoimmune animal models [12,13,14,15,16,17,18,19,20]. In mice with experimental autoimmune encephalomyelitis (EAE), TRAIL blockade [14] or TRAIL deficiency [21] increased neuroinflammation and enhanced disease activity, while inflammation was inhibited using genetically modified TRAIL-expressing cells [22] or TWEAK receptor-TRAIL fusion protein [23]. The mechanism of TRAIL-mediated inhibition of inflammation and autoimmunity is still not clear
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