CD8+ T cell impairment drives severe human metapneumovirus respiratory disease in aged mice.

Abstract

Abstract Objective Human metapneumovirus (HMPV) is a leading cause of severe respiratory disease in children <5, adults >65, and the immunocompromised. CD8+ T lymphocytes are the primary cell responsible for clearing HMPV infection in the lung. We tested the hypothesis that CD8+ T cell impairment in the aged host drives severe respiratory infection and delayed viral clearance. Methods B6 aged 72–73wk mice and young 6–7wk mice were infected with 2×106 PFU HMPV. Seven days post infection, mice were euthanized and lung, bronchoalveolar lavage (BAL), spleen, and draining lymph nodes were collected for flow cytometry. Lung and BAL supernatant was collected for viral titer, histology, and cytokine measurement. Results Aged mice lost more weight, had delayed viral clearance, and increased clinical scores and lung histopathology. Aged mice produced fewer HMPV-tetramer+ cells in lung and BAL. Aged CD8+ T lymphocytes in BAL co-expressed inhibitory receptors PD-1, TIM-3, LAG-3, and 2B4. Aged CD8+ T lymphocytes also upregulated senescence markers, T-bet and EOMES. Upon ex vivo peptide stimulation, aged CD8+ T cells produced significantly less granzyme B compared to young CD8+ T cells. Adoptive transfer of young T cells into aged mice rescued this severe disease phenotype. Young CD8+ cells in the aged host produced more tetramer+ cells and granzyme B and had less senescent marker expression. Conclusion Aged mice exhibit more severe respiratory disease when infected with HMPV. Aged CD8+ T cells appear to be impaired and upregulate senescence markers that contribute to severe HMPV infection in the aged host. Supported by: NIH/NIAID 5R01 AI085062-09, John V. Williams, MD NIH T32GM008208 Medical Scientist Training Program, University of Pittsburgh School of Medicine