Novel HLA-B7-restricted human metapneumovirus epitopes enhance viral clearance in mice and are recognized by human CD8+ T cells

Abstract

Human metapneumovirus (HMPV) is a leading cause of acute lower respiratory tract illness in children and adults. Repeated infections are common and can be severe in young, elderly, and immunocompromised persons due to short-lived protective humoral immunity. In turn, few protective T cell epitopes have been identified in humans. Thus, we infected transgenic mice expressing the common human HLA MHC-I allele B*07:02 (HLA-B7) with HMPV and screened a robust library of overlapping and computationally predicted HLA-B7 binding peptides. Six HLA-B7-restricted CD8+ T cell epitopes were identified using ELISPOT screening in the F, M, and N proteins, with M195–203 (M195) eliciting the strongest responses. MHC-tetramer flow cytometric staining confirmed HLA-B7 epitope-specific CD8+ T cells migrated to lungs and spleen of HMPV-immune mice. Immunization with pooled HLA-B7-restricted peptides reduced viral titer and protected mice from virulent infection. Finally, we confirmed that CD8+ T cells from HLA-B7 positive humans also recognize the identified epitopes. These results enable identification of HMPV-specific CD8+ T cells in humans and help to inform future HMPV vaccine design.

Clinical human metapneumovirus isolates show distinct pathogenesis and inflammatory profiles but similar CD8 + T cell impairment

“…Next, we compared differences in CD8 + T cells (T CD8 ) among clinical isolates, which play a major role in facilitating HMPV clearance ( 12 – 14 ). HMPV infection leads not only to recruitment of T CD8 to the lung but also to induction of virus-specific T CD8 that becomes acutely impaired in the response to infection ( 15 ).…”

“…Interestingly, we saw a clear correlation between HMPV disease and levels of T-cell chemoattractant CXCL9. Several groups, including ours, have demonstrated the importance of T cells and specifically T CD8 in mediating HMPV airway disease ( 13 ) and facilitating HMPV clearance ( 12 , 14 ). We previously described a PD-1-driven acute impairment phenotype in A2 HMPV ( 16 , 17 ).…”