Bars depict the meanSE FasL and TRAIL molecules have been shown to mediate AICD [12,15]

Bars depict the meanSE FasL and TRAIL molecules have been shown to mediate AICD [12,15]. CD4+ T cells, from cancer patients underwent AICD. Blocking FasL/Fas pathway protected from AICD. Upregulation of FasL and TRAIL expressions was found in pleural effusion CD8+ T cells, which also showed a subset of Bcl-2 low cells. In memory CD8+ T cells, AICD depended on both extrinsic and intrinsic apoptotic pathways. Hence,in the pleural space of lung cancer patients, AICD might compromise the antitumor function of CD8+ T cells. Keywords:Activation-induced cell death, CD8+ T cells, Lung cancer, Pleural effusion, Bcl-2 molecule, Fas ligand (FasL), Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) == Introduction == Lung cancer is the second most common form of cancer and the leading cause of cancer death worldwide [1,2]. Pleural effusion is a frequent clinical manifestation of metastatic lung tumors, and Eicosapentaenoic Acid high numbers of mononuclear cells and tumor cells are frequently found within this fluid [35]. Because CD8+ T cells play a key role in the antitumor immune response, tumors have developed mechanisms to circumvent the immune system by suppressing antitumor CD8+ T cell activity [57]. T cell apoptosis has been proposed to severely compromise antitumor function of the host immune system and contributes to tumor progression [812]. Several mechanisms have been proposed for explaining T cell apoptosis. Spontaneous apoptosis of CD3+ T cells in peripheral blood from cancer patients (e.g., breast carcinoma, head and neck cancer, and oral carcinoma) is associated with high levels of Fas expression [10,11]. The binding of Fas ligand (FasL) on the tumor cell to the Fas receptor on the T cell, a hypothesis known as tumor counterattack, has been suggested to be responsible for T cell death [8,9]. However, T cell apoptosis still occurs in some types of tumors, including lung carcinomas, which do not express functional FasL [8,12,13]. Alternatively, chronic immune cell activation can lead to exhaustion of T cells in some chronic infections (e.g., HIV and HBV infections) [12]. One mechanism of T cell exhaustion is mediated by activation-induced cell death (AICD) [12,14]. AICD is mediated by Fas/FasL interactions, which provoke T cells to kill each other and themselves [1416]. Two types of Fas-mediated apoptotic signaling pathways have been described according to the type of cell involved. Type I cells are characterized by a high level of formation Eicosapentaenoic Acid of the Fas-death-induced signaling complex (DISC) and activated caspase-8, which activates the downstream effector caspases. In type II cells, lower amounts of Fas-DISC are formed, leading to lower levels of activated caspase-8. This reduction is compensated by an amplification loop through the Eicosapentaenoic Acid activation of the intrinsic pathway, in which caspase-8 cleaves Bid to generate truncated Bid (tBid). tBid then migrates to the mitochondria and induces the release of cytochromecinto the cytosol. This is followed by the formation of the RELA apoptosome and caspase-9 activation and subsequent activation of effector caspases, leading to cell death [14,16]. Type II apoptotic signaling, compared to type I signaling, can be blocked by high expression of anti-apoptotic Bcl-2 family members, such as Bcl-2 or Bcl-XL. In contrast, in type I cells, Fas-induced apoptosis cannot be blocked by the expression of Bcl-2 or Bcl-XL[14,16]. In cancer patients, AICD has been hypothesized to mediate apoptosis of tumor-infiltrating lymphocytes (TIL) [12,17,18]. In some murine.