Extensive T cell cross-reactivity between diverse seasonal influenza strains in the ferret model

Adrian J Reber,Jin Hyang Kim,Nedzad Music,Ian York,Shane Gansebom,Jufu Chen

doi:10.1038/s41598-018-24394-z

Abstract

Influenza virus causes widespread, yearly epidemics by accumulating surface protein mutations to escape neutralizing antibodies established from prior exposure. In contrast to antibody epitopes, T cell mediated immunity targets influenza epitopes that are more highly conserved and have potential for cross-protection. The extent of T cell cross-reactivity between a diverse array of contemporary and historical influenza strains was investigated in ferrets challenged with 2009 pandemic H1N1 influenza or the seasonal H3N2 strain, A/Perth/16/2009. Post-challenge cell-mediated immune responses demonstrated extensive cross-reactivity with a wide variety of contemporary and historical influenza A strains as well as influenza B. Responses in peripheral blood were undetectable by 36d post-challenge, but cross-reactivity persisted in spleen. The strongest responses targeted peptides from the NP protein and demonstrated cross-reactivity in both the CD4+ and CD8+ T cell populations. Cross-reactive CD4+ T cells also targeted HA and NA epitopes, while cross-reactive CD8+ T cells targeted internal M1, NS2, and PA. T cell epitopes demonstrated extensive cross-reactivity between diverse influenza strains in outbred animals, with NP implicated as a significant antigenic target demonstrating extensive cross-reactivity for both CD4+ and CD8+ T cells.

Highlights

Current influenza vaccines are designed to elicit strain-specific neutralizing antibody primarily against hemagglutinin (HA) and neuraminidase (NA), the major surface antigens of influenza viruses
To form a basic understanding of influenza T cell epitope cross-reactivity, HLA class I and II binding epitopes derived from viral proteins of a diverse group of influenza viruses were downloaded from the Internet Epitope Database (IEDB: http://www.iedb.org/)
T cell responses to influenza viruses are less well understood than are the antibody responses, but there is some evidence for broadly cross-reactive T cell immunity

Summary

Introduction

Current influenza vaccines are designed to elicit strain-specific neutralizing antibody primarily against hemagglutinin (HA) and neuraminidase (NA), the major surface antigens of influenza viruses. Occasional emergence of viruses with novel HA and NA from animal reservoirs results in pandemic strains with significantly mismatched surface antigens that are resistant to antibody mediated neutralization directed against the seasonal viruses. These issues have led to intense interest in vaccines inducing broadly cross-protective immunity to influenza viruses. In contrast to antibody epitopes which recognize primarily the hydrophilic, 3-dimensional outer surface of proteins, T cell epitopes are primarily composed of linear 8 to 24 amino acid peptides derived from internal proteins and the internal, hydrophobic regions of external proteins[2,3] These regions are more conserved between influenza subtypes and could confer immunity to heterologous as well as homologous influenza virus[2,3,4,5]. The concern over the ability of mice to adequately mimic the diverse array of human diseases, immune responses, and drug toxicity has prompted more effort to develop animal models which more closely reflect the human condition on a disease specific basis[7,8,9]

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