The Contraction Phase of Virus-Specific CD8+ T Cells Is Unaffected by a Pan-Caspase Inhibitor

Abstract

The effectiveness of protection conferred by CD8+ memory T cells is determined by both their quality and their quantity, which suggests that vaccine efficacy might be improved if it were possible to increase the size of the memory pool. Approximately 90% of virus-specific CD8+ T cells die during the contraction phase and, herein, we have attempted to increase the memory pool by reducing CD8+ T cell death. CD8+ T cell contraction has been attributed to apoptosis, or programmed cell death (PCD), which, classically, is dependent on caspases. Caspase-dependent PCD can be prevented by the pan-caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp (OMe)-fluoromethylketone (zVAD), and here we evaluate the effect of this compound on virus-specific T cell responses in mice. zVAD prevented caspase-dependent PCD of freshly isolated virus-specific T cells in tissue culture, and a fluorescent analog, FITC-VAD, entered CD8+ T cells following in vivo injection. However, despite using 11 different regimens of zVAD administration in vivo, no significant effects on CD8+ or CD4+ memory T cell numbers were observed. Furthermore, the CD8+ memory T cell responses to secondary virus infection were indistinguishable, both qualitatively and quantitatively, in zVAD-treated and normal mice. The absence of effect cannot be attributed to a technical flaw, because identical doses of zVAD were able to rescue mice from hepatocyte apoptosis and lethal intrahepatic hemorrhage, induced by inoculation of anti-Fas Ab. We conclude that the contraction phase of the virus-specific T cell response is unlikely to require caspase-dependent PCD. We propose that contraction can be mediated by an alternative, caspase-independent pathway(s).

Intrinsic and extrinsic control of effector T cell survival and memory T cell development

“…Data from another study suggested that eVector T cell death can occur independent of mitochondrial cytochrome C activation of apaf-1 and the apoptosome [36]. Moreover, using a pan-caspase chemical inhibitor, one study suggested that T cell contraction is largely independent of caspase activation altogether, which is consistent with recent studies that indicate that cell death during thymic selection is independent of eVector caspases 3 and 7 [8,37]. Increased reactive oxygen species (ROS) may also predispose T cells to death and an inhibitor of ROS has been shown to increase the ex vivo survival of activated CD4 T cells [38].…”

Viral Cell Death Inhibitor MC159 Enhances Innate Immunity against Vaccinia Virus Infection

“…Similarly, MC159 transgenic lymphocytes exhibited normal cell death markers, such as annexin V and TUNEL, during VV infection. These results are reminiscent of the lack of inhibition of CD8 ϩ T-cell death by pan-caspase inhibitors during VV infection (35). Although we cannot rule out the possibility that the transgenic lymphocytes could still undergo programmed necrosis, our results do indicate that the enhanced ␥␦ T-cell infiltration and innate immune control in MC159 transgenic mice during VV infection could not be attributed to inhibition of apoptosis.…”

Role of Bim in Regulating CD8+T-Cell Responses during Chronic Viral Infection

“…This equal effect across all epitopes is different from chronic LCMV infection, where the number of NP396-404 specific T cells is affected to the greatest extent. How Bim facilitates the contraction process is unclear because treatment with caspase inhibitors does not block contraction of cells following LCMV infection (29).…”