Engineering T Cells Specific for a Dominant Severe Acute Respiratory Syndrome Coronavirus CD8 T Cell Epitope

Severe acute respiratory syndrome (SARS) is a highly contagious and life threatening disease, with a fatality rate of almost 10%. The etiologic agent is a novel coronavirus, severe acute respiratory syndrome coronavirus (SARS-CoV), with animal reservoirs found in bats and other wild animals and thus the possibility of reemergence. In this study, we first investigated at 6 years postinfection whether SARS-specific memory T cells persist in SARS-recovered individuals, demonstrating that these subjects still possess polyfunctional SARS-specific memory CD4(+) and CD8(+) T cells. A dominant memory CD8(+) T cell response against SARS-CoV nucleocaspid protein (NP; amino acids 216 to 225) was then defined in SARS-recovered individuals carrying HLA-B*40:01, a HLA-B molecule present in approximately one-quarter of subjects of Asian ethnicities. To reconstitute such a CD8(+) T cell response, we isolated the alpha and beta T cell receptors of the HLA-B*40:01-restricted SARS-specific CD8(+) T cells. Using T cell receptor gene transfer, we generated SARS-specific redirected T cells from the lymphocytes of normal individuals. These engineered CD8(+) T cells displayed avidity and functionality similar to that of natural SARS-specific memory CD8(+) T cells. They were able to degranulate and produce gamma interferon, tumor necrosis factor alpha, and macrophage inflammatory proteins 1 alpha and 1 beta after antigenic stimulation. Since there is no effective treatment against SARS, these transduced T cells specific for an immunodominant SARS epitope may provide a new avenue for treatment during a SARS outbreak.