CD8 low CD100 − T Cells Identify a Novel CD8 T Cell Subset Associated with Viral Control during Human Hantaan Virus Infection

Abstract

ABSTRACT Hantaan virus (HTNV) infection can cause a severe lethal hemorrhagic fever with renal syndrome (HFRS) in humans. CD8 + T cells play a critical role in combating HTNV infections. However, the contributions of different CD8 + T cell subsets to the immune response against viral infection are poorly understood. Here, we identified a novel subset of CD8 + T cells characterized by the CD8 low CD100 − phenotype in HFRS patients. The CD8 low CD100 − subset accounted for a median of 14.3% of the total CD8 + T cells in early phase of HFRS, and this percentage subsequently declined in the late phase of infection, whereas this subset was absent in healthy controls. Furthermore, the CD8 low CD100 − cells were associated with high activation and expressed high levels of cytolytic effector molecules and exhibited a distinct expression profile of effector CD8 + T cells (CCR7 +/− CD45RA − CD127 high CD27 int CD28 low CD62L − ). When stimulated with specific HTNV nucleocapsid protein-derived peptide pools, most responding CD8 + cells (gamma interferon [IFN-γ] positive and/or tumor necrosis factor alpha [TNF-α] positive) were CD8 low CD100 − cells. The frequency of CD8 low CD100 − cells among HTNV-specific CD8 + T cells was higher in milder cases than in more severe cases. Importantly, the proportion of the CD8 low CD100 − subset among CD8 + T cells in early phase of HFRS was negatively correlated with the HTNV viral load, suggesting that CD8 low CD100 − cells may be associated with viral clearance. The contraction of the CD8 low CD100 − subset in late phase of infection may be related to the consistently high expression levels of PD-1. These results may provide new insights into our understanding of CD8 + T cell-mediated protective immunity as well as immune homeostasis after HTNV infection in humans. IMPORTANCE CD8 + T cells play important roles in the antiviral immune response. We found that the proportion of CD8 low CD100 − cells among CD8 + T cells from HFRS patients was negatively correlated with the HTNV viral load, and the frequency of CD8 low CD100 − cells among virus-specific CD8 + T cells was higher in milder HFRS cases than in more severe cases. These results imply a beneficial role for the CD8 low CD100 − cell subset in viral control during human HTNV infection.