Activation‐induced cell death: The controversial role of Fas and Fas ligand in immune privilege and tumour counterattack

Abstract

Summary Activation-induced cell death (AICD) is the process by which cells undergo apoptosis in a controlled manner through the interaction of a death factor and its receptor. Programmed cell death can be induced by a number of physiological and pathological factors including Fas (CD95)-Fas ligand (FasL/CD95L) interaction, tumour necrosis factor (TNF), ceramide, and reactive oxygen species (ROS). Fas is a 48-kDa type I transmembrane protein that belongs to the TNF/nerve growth factor receptor superfamily. FasL is a 40-kDa type II transmembrane protein that belongs to the TNF superfamily. The interaction of Fas with FasL results in a series of signal transductions which initiate apoptosis. The induction of apoptosis in this manner is termed AICD. Activation-induced cell death and Fas-FasL interactions have been shown to play significant roles in immune system homeostasis. In this review the involvement of Fas and Fas ligand in cell death, with particular reference to the T cell, and the mechanism(s) by which they induce cell death is described. The role of AICD in immune system homeostasis and the controversy surrounding the role of FasL in immune privilege, inflammation, and so-called tumour counterattack is also discussed.

The mitochondrial dynamics in cancer and immune-surveillance

“…Depolarized mitochondria are targeted for mitophagy but, due to an early block of general autophagy, they are not removed, accumulate in the cell and amplify CytC release, thus priming cell death [213]. Tumor cells in the TME can increase FasL expression, thus promoting AICD in Fas Receptor-expressing cytotoxic T lymphocytes [214]. This tumor cell counterattack may limit the T cell anti-tumor immune response, thereby favouring cancer immune escape.…”

The FAS ligand promoter polymorphism, rs763110 (−844C>T), contributes to cancer susceptibility: evidence from 19 case–control studies

“…1 Many studies indicate that AICD is an important mechanism responsible for the increased apoptosis rate among the tumor-infiltrating lymphocytes, leading to the transformed cells escaping the elimination by anticancer immunosurveillance and, therefore, AICD contributes to cancer development. 2,3 Activation-induced cell death is a FAS ligand (FASL)-dependent process, and the increased expression of FASL can cause AICD in peripheral T cells. 4 Antigenic stimulation of cancer within the tumor microenvironment can induce tumor-infiltrating lymphocytes to overexpress FASL and subsequently lead to suicide or fratricide of tumor-infiltrating lymphocytes through the FAS -FASL interaction-triggered apoptosis.…”

Adenovirus expressing Fas ligand gene decreases airway hyper-responsiveness and eosinophilia in a murine model of asthma

“…17 Fas (CD95), the receptor signaling component of apoptosis, is expressed either constitutively or after activation in a variety of immune cells, such as T cells, B cells, monocytes/macrophages, NK cells, neutrophils, and eosinophils. 18 The other essential component involved in the Fas-mediated apoptotic pathway is the Fas ligand (FasL, CD95L). Identified as a type II membrane protein member of the tumor necrosis factor family of ligands, FasL was originally characterized in T cells as the primary effector molecule of Th1 cytotoxicity.…”