Lymphopenia Associated with Highly Virulent H5N1 Virus Infection Due to Plasmacytoid Dendritic Cell-Mediated Apoptosis of T Cells

Although lymphopenia is a hallmark of severe infection with highly pathogenic H5N1 and the newly emerged H7N9 influenza viruses in humans, the mechanism(s) by which lethal H5N1 viruses cause lymphopenia in mammalian hosts remains poorly understood. Because influenza-specific T cell responses are initiated in the lung draining lymph nodes (LNs), and lymphocytes subsequently traffic to the lungs or peripheral circulation, we compared the immune responses in the lung draining LNs postinfection with a lethal A/HK/483/97 or nonlethal A/HK/486/97 (H5N1) virus in a mouse model. We found that lethal H5N1, but not nonlethal H5N1, virus infection in mice enhances Fas ligand (FasL) expression on plasmacytoid dendritic cells (pDCs), resulting in apoptosis of influenza-specific CD8(+) T cells via a Fas-FasL-mediated pathway. We also found that pDCs, but not other DC subsets, preferentially accumulate in the lung draining LNs of lethal H5N1 virus-infected mice, and that the induction of FasL expression on pDCs correlates with high levels of IL-12p40 monomer/homodimer in the lung draining LNs. Our data suggest that one of the mechanisms of lymphopenia associated with lethal H5N1 virus infection involves a deleterious role for pDCs.