Function and regulation of the CD95 (APO-1/Fas) ligand in the immune system

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Abstract

CD95/CD95L mediated apoptosis is an important mechanism of immune homeostasis. It is instrumental for termination of an immune response and mainly be involved in peripheral tolerance. Dysregulation of the CD95/CD95L system leads to severe diseases. In this review, we present a survey of the role of the CD95/CD95L system in the immune system and, particularly, focus on the signals and transcription factors (NF-AT, Egr, NF-κB, AP-1, c-Myc, Nur77, IRFs, SP-1, ALG-4, RORγt, and CIITA) involved in CD95L expression. It should also be evident from this review that a profound insight into the molecular mechanisms of CD95L activation should allow to explore potential therapeutic means to treat CD95/CD95L-dependent diseases.

Introduction

Our immune system protects us from infections by microorganisms and parasites. Upon an immune response, antigen-specific lymphocytes in the periphery are rapidly expanded to fight against infections. However, once the infection is cleared, the antigen-reactive lymphocytes are no longer needed and have to be removed. Only a small fraction of the antigen-reactive lymphocytes remain as memory cells. We now know that the other lymphocytes are removed via apoptosis, the most common form of eucaryotic cell death. Also in the thymus, more than 95% of immature thymocytes are deleted by apoptosis during thymic selection to eliminate useless or potential autoreactive cells. Thus, in both the central immune compartments and peripheral apoptosis plays an essential role in maintenance of tolerance and in termination of an ongoing immune response [1]. Deregulation of apoptosis contributes to many diseases including autoimmunity, cancer, stoke, drug resistance in tumors, and the acquired immunodeficiency syndrome (AIDS).

Section snippets

CD95 (APO-1/Fas) and its ligand CD95L

Apoptosis mediated by interaction of CD95 and its ligand CD95L is one of the best understood apoptotic system in T cells. CD95 is a 45-kDa type I transmembrane protein and belongs to the tumor necrosis factor (TNF) receptor family [2], [3], [4]. CD95 is widely expressed in various tissues with particularly abundant expression in thymocytes and T cells [5], [6]. In resting B cells, CD95 is not present and is expressed upon induction by CD40 ligand and endotoxins [7], [8], [9]. The ligand of

CD95/CD95L mutations and autoimmune diseases

The biologic function of CD95/CD95L has been clearly demonstrated by mice genetically defect in either the CD95 (lpr, lprcg) or the CD95L (gld) gene. The mice lacking functional expression of CD95 and CD95L develop a systemic lupus erythematosus-like autoimmune disease [14], [15]. Similar to the autoimmune diseases in lpr/gld mice, autoimmune lymphoproliferative syndromes were also reported in patients with mutations in the CD95 or CD95L gene [16], [17], [18], [19], [20]. Apparently, CD95/CD95L

Signals through the T-cell receptor (TCR)/CD3

CD95L is not present in resting T cells and is highly expressed upon stimulation of T cells by cross-linking of TCR/CD3 with antigens or by reagents that mimic the antigen signal. The earliest signaling events following TCR/CD3 engagement are the sequential activation of tyrosine kinases (TPKs) including Lck and ZAP-70. ZAP-70 and Lck are shown to be involved in up-regulation of CD95L expression in activation-induced apoptosis [52], [53]. Both Lck and ZAP-70 are required for calcium

Structure of the CD95L promoter

Transcriptional activation of the CD95L gene in T cells occurs rapidly. CD95L mRNA can be detected as early as 1 h following αCD3/αCD28 or PMA/ionomycin stimulation and reaches a maximum after 4 h [78]. Jurkat T cells have been used extensively as a model for CD95-mediated AICD [79] and are frequently used for delineation of the cis-regulatory regions controlling human CD95L gene expression. We and others have identified a series of promoter regulatory elements located within a 960 bp fragment

Protection of T cells from AICD by vitamin E

In addition to TCR stimulation NF-κB and AP-1 activities can be induced by a vast array of stimuli including certain environmental stressors such as phorbol esters (e.g. PMA), chemicals, ionizing and UV irradiation, chemotherapeutic agents, and proto-oncogenes [132], [133]. An oxidation/reduction (redox) model has been suggested whereby the diverse agents that activate NF-κB and AP-1 do so by increasing oxidative stress within the cells [132] (Fig. 4). Although some controversial data cannot be

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