br Acknowledgements We thank Kathy Spindler

Acknowledgements We thank Kathy Spindler for helpful review of the manuscript. Expert technical assistance from Joel Whitfield in the University of Michigan Cancer Center Immunology Core is greatly appreciated. This research was supported by the American Heart Association (16GRNT30250013) and by a University of Michigan Charles Woodson Accelerator Award.
Introduction Upon encountering a pathogenic microbe, naive antigen (Ag)-specific CD8+ T IU1 proliferate and differentiate into effector CD8+ T cells during the expansion phase. Most activated T cells subsequently die by apoptosis during the contraction phase, but a few survive to become memory cells, which persist for a long period of time (Wong and Pamer, 2003; Ahmed and Gray, 1996; Schluns and Lefrancois, 2003). However, in chronic antigen stimulation, such as that occurs with chronic infections or tumors, CD8+ T cells become exhausted, and thus, dysfunctional, resulting in failure to eliminate the bacteria or cancer (Barber et al., 2006; Wherry et al., 2007; Wherry and Kurachi, 2015; Pauken and Wherry, 2015). This exhaustion is characterized by a decreased proliferative capacity, loss of cytokine secretion, reduced cytotoxic killing abilities, and phenotypic changes, as well as an increase in inhibitory receptors, including programmed cell death protein 1 (PD-1), all of which can be restored by blockading the inhibitory receptors of the exhausted CD8+ T cells (Kim and Ahmed, 2010; Sakuishi et al., 2010; Ostrand-Rosenberg et al., 2014). Although the exhausted T cells may be physically deleted through apoptosis, the fate of Ag-specific activated CD8+ T cells in tumor immune response remains unclear. Because the number of Ag-specific effector CD8+ T cells is dependent on the number of T cells that survive apoptosis, identification of the molecular mechanisms responsible for activated T cell apoptosis following continuous T cell antigen receptor (TCR)-mediated activation is important for understanding how effector cells survive during the tumor immune response. Primary TCR-mediated activation can result in at least two types of cell death in activated T cells, activation-induced cell death (AICD) (Schluns and Lefrancois, 2003), also known as Ag-driven apoptosis, and activated T cell autonomous cell death (ACAD), also known as growth factor withdrawal-induced apoptosis (Marrack and Kappler, 2004; Hildeman et al., 2002a; Marsden and Strasser, 2003). Previous studies have shown that ACAD is responsible for the death of the majority of activated T cells responding to a foreign Ag (Ostrand-Rosenberg et al., 2014; Schluns and Lefrancois, 2003; Marsden and Strasser, 2003) but that this can be prevented by the enforced expression of Bcl-2, indicating that the upregulation of Bcl-2 in effector T cells plays a critical role in preventing activated T cell death by ACAD during the contraction phase (Hildeman et al., 2002a; Pellegrini et al., 2003; Van Parijs et al., 1998) Common γ cytokines such as IL-15 and IL-7 have been shown to play a critical role in the upregulation of Bcl-2 and the survival of effector CD8+ T cells during the contraction phase of acute bacterial infection (Nakajima et al., 1997; Vella et al., 1998; Gett et al., 2003; Yajima et al., 2006). However, the expression of memory markers, such as the IL-7 receptor α chain (CD127), is decreased in exhausted CD8+ T cells upon chronic Ag stimulation against a tumor (Kim and Ahmed, 2010; Sakuishi et al., 2010; Ostrand-Rosenberg et al., 2014). Therefore, commonγ cytokines such as IL-7 may not prevent apoptosis in exhausted CD8+ T cells during the tumor immune response. The other kind of cell death, AICD, is mainly triggered through cell surface proteins of the tumor necrosis factor (TNF) receptor family, including Fas (Ju et al., 1995; Sytwu et al., 1996; Nagata and Suda, 1995). Cross-linking of Fas via ligation by the Fas ligand (FasL) activates the Fas-associated death domain, which triggers the activation of intracellular caspases, leading to apoptosis (Ashkenazi and Dixit, 1998). Previous studies using Fas/FasL mutants or Fas/tumor necrosis factor 1 (TNFR1)-deficient mice have demonstrated that either Fas/FasL or TNFR1 is required for T cell death during chronic infections (Zhou et al., 2002). Therefore, it is possible that apoptosis of exhausted CD8+ T cells is induced by AICD following the continuous stimulation by a tumor antigen during the tumor immune response.