Astrocytic Fas ligand expression is required to induce T‐cell apoptosis and recovery from experimental autoimmune encephalomyelitis

Abstract

In T-cell-mediated autoimmune diseases of the CNS, apoptosis of FasKeywords: Autoimmunity r Astrocytes r EAE r FasL Additional supporting information may be found in the online version of this article at the publisher's web-site Introduction EAE is a widely used animal model to study MS, an inflammatory demyelinating disease mediated by accumulation of T lymphocytes and macrophages in the CNS [1,2]. EAE can be induced by either active immunization with myelin Ags including myelin oligodendrocyte glycoprotein (MOG) peptide or passive transfer of myelin-reactive CD4 + T cells, which are both initiators and Correspondence: Prof. Dirk Schlüter e-mail: dirk.schlueter@med.ovgu.de effectors of EAE. Among CD4 + T lymphocytes, GM-CSF-producing CD4 + T cells, IFN-γ-secreting Th1 cells, and IL-17-secreting Th17 cells have been identified as the most important mediators in the immunopathogenesis of EAE [3][4][5][6] and all of them can induce EAE independently, although recent studies point to an essential role of GM-CSF-producing CD4 + T cells, which can induce EAE independent of . Infiltrating T lymphocytes trigger an inflammatory response in the CNS culminating in demyelination and axonal damage clinically resulting in paralysis [8]. Correspondingly, recovery from EAE requires termination of inflammation and the induction of T-cell apoptosis in the CNS [9].www.eji-journal.eu 116Xu Wang et al. Eur. J. Immunol. 2013. 43: 115-124 Fas ligand (FasL; CD95L), a cytotoxic cytokine belonging to the TNF superfamily, acts through Fas, a death receptor of the TNFR superfamily, to induce programed cell death via caspase signaling [10]. Local expression of FasL in immunoprivileged organs including eyes, testis, and placenta is essential for deletion of infiltrating inflammatory cells [11][12][13]. Fas/FasL interaction is of particular importance for homeostasis of the immune system and its dysregulation has been implicated in various autoimmune diseases. Mice carrying autosomal recessive mutations in the Fas (lpr) and FasL (gld) genes develop a spontaneous autoimmune syndrome similar to human systemic lupus erythematosus [14,15]. Fas and FasL are also involved in the pathogenesis of EAE, as EAE is dramatically ameliorated in lpr and gld mice in terms of disease incidence and mean clinical score [16]. Intrathecal infusion of recombinant FasL induces apoptosis of CNS-infiltrating inflammatory cells, including T cells and macrophages, but does not exert cytotoxicity against CNS-resident cells, resulting in mitigated EAE manifestations [17].Elimination of infiltrating T cells in the CNS by Fas/FasLmediated apoptosis is crucial for resolution of EAE [9,18,19], since FasL-deficient gld recipients develop prolonged EAE after adoptive transfer of myelin basic protein-reactive WT Fas + T lymphocytes [20]. The CNS-resident cell population which induces apoptosis of CD4 + T cells in EAE still remains to be identified. We hypothesize that astrocytes, which constitutively express FasL, may play a key role given that FasL-expressing astrocytes a...

Differential expression of interferon-γ and chemokine genes distinguishes Rasmussen encephalitis from cortical dysplasia and provides evidence for an early Th1 immune response

“…On the other hand, the detection of FasL transcripts in the present study could be explained by activation-induced cell death of activated T cells in the brain [54]. In experimental autoimmune encephalitis, astrocytes expressing FasL have been implicated in T cell homeostasis [55]. …”

Serpins Promote Cancer Cell Survival and Vascular Co-Option in Brain Metastasis

“…FasL is highly expressed in reactive astrocytes in ischemia, brain trauma, Alzheimer’s disease, encephalomyelitis and multiple sclerosis (Choi and Benveniste, 2004). Astrocytes are the main source of FasL against invading T cells in encephalomyelitis (Wang et al, 2013). Plasmin cleaves FasL at Arg144, releasing sFasL as a diffusible cell death signal (Bajou et al, 2008; Fang et al, 2012).…”

Interaction of astrocytes and T cells in physiological and pathological conditions

“…It has been revealed that TNF-treated astrocytes up-regulates Galectin-9 to promote encephalitogenic T-cell apoptosis (Steelman et al, 2013). Xu Wang et al (Wang et al, 2013) used GFAP-Cre FasL fl/fl mice in EAE model and concluded that astrocytes induced apoptosis of Fas + activated CD4 + T cells and to increase numbers of Foxp3 + Treg cells beyond the time point of maximal clinical disease. The FasL expression on astrocytes and its role in induction of T cell apoptosis have also been documented in other literatures.…”