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  • The other type of cell

    2021-09-18

    The other type of cell death that occurs in activated T nkh receptor is caused by growth factor withdrawal following TCR-mediated activation, whereby most of the activated T cells die by apoptosis following the eradication of bacteria during an acute infection in order to reduce the level of cytokine production. Several studies have shown that the upregulation of Bcl-2 in effector T cells via common γ cytokine signaling (including IL-2, IL-7, and IL-15) plays a critical role in preventing activated T cell death during the contraction phase of an acute bacterial infection (Hildeman et al., 2002b; Pellegrini et al., 2003; Van Parijs et al., 1998; Nakajima et al., 1997; Vella et al., 1998; Gett et al., 2003; Yajima et al., 2006). Furthermore, it has previously been reported that rIL-2 administration increases the numbers of exhausted CD8+ T cells during a chronic lymphocytic choriomeningitis virus (LCMV) infection (West et al., 2013) and we have shown that in vivo rIL-15 administration increases the number of Ag-specific activated CD8+ T cells during BCG-OVA infection as a model of chronic infection (Tang et al., 2009). Therefore, these mechanisms of growth factor withdrawal-induced apoptosis will also have been involved in the death of the exhausted Ag-specific CD8+ T cells during the tumor immune response. However, the enforced expression of Bcl-2 could not rescue the Ag-specific CD8+ T cells following EG.7 inoculation. Furthermore, it has previously been shown that the expression pattern of IL-7Rα and IL-2Rβ is consistent with the gene-expression data, suggesting that exhausted CD8+ T cells will not efficiently respond to IL-2, IL-4, IL-7, and IL-15 during a chronic infection (Barber et al., 2006; Wherry et al., 2007), and we also failed to detect the expression of IL-7Rα and IL-2Rβ in exhausted CD8+ T cells following EG.7 inoculation (Supplemental Fig.1). We conclude that the upregulation of Bcl-2 is not involved in preventing the apoptosis of exhausted CD8+ T cells during the tumor immune response. Several previous studies have investigated the anti-tumor immunity of Fas or FasL mutant mice using several tumor cell lines and have found that although the FasL-cytolytic pathway of activated T cells plays a critical role in the eradication of Fas-expressing tumor cells (O’Reilly et al., 2009), the anti-tumor immunity of FasL and Fas mutant mice is comparable to that of wild type mice using both a model of local tumor growth after s.c. inoculation (Hashimoto et al., 1999; Zhang et al., 2009) and lung colonization after intravenous injection (Yang et al., 2012; Winter et al., 1999; Smyth et al., 1999). Moreover, it has been shown that tumor growth is retarded in gld mice compared with control mice (Cao et al., 2015), as corroborated here, and that tumor growth of renal cell adenocarcinoma cell lines expressing the influenza viral hemagglutinin as a model tumor Ag were markedly induced in FasL-dysfunctional gld mice but retarded in Fas-dysfunctional lpr mice compared with control mice (Shanker et al., 2009). Therefore, it is possible that several mechanisms are involved in anti-tumor immunity of Fas and FasL mutant mice depending on the cell lines, hosts, and experimental conditions. The in vivo blockade of Fas signaling of exhausted Ag-specific CD8+ T cells may be useful for cancer immunotherapy. We found that exhausted CD8+ T cells expressed a high level of Fas following EG.7 inoculation, suggesting that antagonistic Fas or FasL antibodies rescue these cells from Fas-induced apoptosis. A previous study reported that intravenous administration of anti-Fas antibodies induces lethal hepatitis in mice (Ogasawara et al., 1993) and a similar toxicity was observed with intravenous administration of anti-FasL antibodies (Rensing-Ehl et al., 1995). However, local injection with anti-Fas Ab has been shown to inhibit tumor growth without inducing hepatitis (Rensing-Ehl et al., 1995). Therefore, the intratumoral administration of anti-FasL nkh receptor or Fas antibodies may be a useful approach for cancer immunotherapy. However, it should be noted that many tumors express Fas at high levels, suggesting that they would be sensitive to Fas-induced apoptosis by FasL-expressing T lymphocytes (Trauth et al., 1989). Therefore, antagonistic Fas antibodies may inhibit the eradication of Fas-expressing tumor cells via the FasL-cytolytic pathways of activated T cells.