Virus-Specific CD4⁺and CD8⁺Cytotoxic T-Cell Responses and Long-Term T-Cell Memory in Individuals Vaccinated against Polio

Abstract

The presence of poliovirus (PV)-specific CD4؉ T cells in individuals vaccinated against polio has been shown, but CD8 ؉ T-cell responses have not been described. Here, we functionally characterize the CD4 ؉ T-cell response and show for the first time that dendritic cells and macrophages can stimulate PV-specific CD8 ؉ T-cell responses in vitro from vaccinees. Both CD4؉ T and CD8 ؉ T cells secrete gamma interferon in response to PV antigens and are cytotoxic via the perforin/granzyme B-mediated pathway. Furthermore, the T cells also recognize and kill Sabin 1 vaccine-infected targets. The macrophage-stimulated CD4 ؉ T and CD8 ؉ T cells most likely represent memory T cells that persist for long periods in vaccinated individuals. Thus, immunity to PV vaccination involves not only an effective neutralizing antibody titer but also long-term CD4؉ and CD8؉ cytotoxic T-cell responses.Immunity to poliovirus (PV) as a result of a vaccination regimen with oral Sabin vaccine (OPV) and/or inactivated Salk vaccine (IPV) has been the focus of many studies. The majority of these studies have been directed towards the protective neutralizing antibody response in various populations worldwide (6,10,15,28,45,49); less attention has been given to adaptive T-cell responses and the probable role of these cells in the resolution of PV infection.T-cell responses to PV have been studied primarily in mice. These studies have identified several epitopes in PV structural proteins that are recognized by murine CD4 and CD8 T cells (17,21,23,26). As normal mice lack the human poliovirus receptor (PVR) and are not, therefore, susceptible to poliovirus infection, the role of the PV-specific T cells in protective immunity in these mice could not be determined. However, adoptive transfers of PV-specific CD4 T cells into PVR-transgenic mice that are susceptible to PV infection showed that CD4 T cells do indeed provide protection against infection by lethal doses of PV and that these CD4 T cells provide help to B cells to produce protective antibodies (26). In contrast, studies identifying PV-specific T cells present in humans, the normal host for PV, have been limited. It is clear that PV-specific CD4 T cells are induced in vaccinated individuals, and some CD4 T-cell epitopes have been defined (13, 43). There are no previous reports that a CD8 T-cell-mediated response to PV is initiated in vaccinated individuals, even following recent IPV boosters (20), or in primates that are susceptible to PV infection.The induction of cytotoxic CD8 T cells is a cornerstone of viral immunity, as CD8 T cells are important in viral clearance. Dendritic cells (DCs) and macrophages (M) are central to the initiation of CD4 and CD8 T-cell responses to pathogens. We have recently shown that these critical antigen-presenting cells (APCs) express PVR and can be productively infected with PV, with kinetics and cytopathology similar to those seen during infection of HeLa cells, and that infection results in apoptotic cell death (48). Several processes that are important in...

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