Parallel T Cell Immunogenic Regions in Influenza B and A Viruses with Distinct Nuclear Export Signal Functions: The Balance between Viral Life Cycle and Immune Escape

Abstract

Influenza A viruses (IAVs) and influenza B viruses (IBVs) cause annual epidemics in human populations with seasonal circulation spikes. Peptide AM58–66GL9 located at residues 58–66 of M1 protein of IAVs has been recognized as an immunodominant T cell epitope with HLA-A*0201 restriction and broadly used as a positive reference in influenza immunity. This peptide also almost completely overlaps with a nuclear export signal (NES) 59–68 in IAV M1, which explains the limited escape mutations under the T cell immune pressure in this region. In this study, we investigated the potential immunogenicity and NES in the corresponding region of IBV. The long peptide covering this region can be recognized by specific T cells and induce robust expression of IFN-γ among HLA-B*1501 donors in vivo, but not in HLA-A*0201 donors. Among a series of truncated peptides derived from this region, we identified an immunodominant HLA-B*1501–restricted T cell epitope BM58–66AF9 (ALIGASICF) in the M1 protein of IBV. Furthermore, the structure of the HLA-B*1501/BM58–66AF9 complex shows that BM58–66AF9 performs a flat and featureless conformation that is similar to AM58–66GL9 presented by HLA-A*0201. In contrast with IAV, the sequence around residues 55–70 of IBV M1 does not contain an NES. Our comparative study on IBVs and IAVs provides new insights into the immune and evolution characteristics of IBVs and may shed light on vaccine development for influenza viruses.

Existing Evidence for Influenza B Virus Adaptations to Drive Replication in Humans as the Primary Host

“…After IBV infection, cell lines stably expressing different HLA-alleles showed significantly decreased MHC Class I surface expression compared to IAV infection [ 82 ]. Another CTL evasion mechanism of IBV is a loss of an immunodominant epitope within a nuclear export signal (NES) in the IBV M1 (B-M1) protein [ 83 ]. This immunodominant epitope is found in the NES of IAV and may represent an adaptive mutation to avoid immune targeting in a conserved functional region [ 83 ].…”

“…Another CTL evasion mechanism of IBV is a loss of an immunodominant epitope within a nuclear export signal (NES) in the IBV M1 (B-M1) protein [ 83 ]. This immunodominant epitope is found in the NES of IAV and may represent an adaptive mutation to avoid immune targeting in a conserved functional region [ 83 ]. While MHC class I downregulation is not unique to IBV infection [ 84 , 85 , 86 ], the apparent importance of human CTL evasion for replication may signal an advantage for IBV that could impact its ability to replicate in other hosts.…”

“…Targeting of human-specific ISG15 by B-NS1 suggests an integral role between IBV replication and the human IFN response during infection. IBV also encodes mechanisms to avoid long-lasting memory CTL responses by downregulating host MHC Class I molecules on the surface of infected cells [ 82 ] and accumulating mutations in the B-M1 protein’s sequence to protect a conserved functional region from an immunodominant CTL epitope [ 83 ]. This effort to evade different aspects of the immune system obviously relates to its importance in promoting viral replication.…”