CD8low CD100- T Cells Identify a Novel CD8 T Cell Subset Associated with Viral Control during Human Hantaan Virus Infection

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-gamma] positive and/or tumor necrosis factor alpha [TNF-alpha] positive) were CD8(low) CD100- cells. The frequency of CD8low 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.