Cross-reactive CD8 ⁺ T-cell immunity between the pandemic H1N1-2009 and H1N1-1918 influenza A viruses

Abstract

Preexisting T-cell immunity directed at conserved viral regions promotes enhanced recovery from influenza virus infections, with there being some evidence of cross-protection directed at variable peptides. Strikingly, many of the immunogenic peptides derived from the current pandemic A(H1N1)-2009 influenza virus are representative of the catastrophic 1918 “Spanish flu” rather than more recent “seasonal” strains. We present immunological and structural analyses of cross-reactive CD8 + T-cell–mediated immunity directed at a variable (although highly cross-reactive) immunodominant NP 418–426 peptide that binds to a large B7 family (HLA-B*3501/03/0702) found throughout human populations. Memory CD8 + T-cell specificity was probed for 12 different NP 418 mutants that emerged over the 9 decades between the 1918 and 2009 pandemics. Although there is evidence of substantial cross-reactivity among seasonal NP 418 mutants, current memory T-cell profiles show no preexisting immunity to the 2009-NP 418 variant or the 1918-NP 418 variant. Natural infection with the A(H1N1)-2009 virus, however, elicits CD8 + T cells specific for the 2009-NP 418 and 1918-NP 418 epitopes. This analysis points to the potential importance of cross-reactive T-cell populations that cover the possible spectrum of T-cell variants and suggests that the identification of key residues/motifs that elicit cross-reactive T-cell sets could facilitate the evolution of immunization protocols that provide a measure of protection against unpredicted pandemic influenza viruses. Thus, it is worth exploring the potential of vaccines that incorporate peptide variants with a proven potential for broader immunogenicity, especially to those that are not recognized by the current memory T-cell pool generated by exposure to influenza variants that cause successive seasonal epidemics.

Vaccination with NS1-truncated H3N2 swine influenza virus primes T cells and confers cross-protection against an H1N1 heterosubtypic challenge in pigs

“…Although influenza-specific T cells do not provide sterilizing immunity, they protect more broadly than neutralizing antibodies against heterologous and heterosubtypic strains through viral clearance [10,11]. Broadly cross-reactive T cell epitopes are typically located in internal proteins of influenza viruses such as the nucleoprotein (NP) and matrix (M1) segments, which are more conserved than the surface hemagglutinin (HA) and NA glycoproteins [12][13][14]. Cellular immunity to influenza in the absence of cross-reactive antibody can markedly reduce viral replication in humans and pigs [15,16].…”

Preexisting CD8 + T-cell immunity to the H7N9 influenza A virus varies across ethnicities

“…We then examined CTL responses to the antigenic peptides unique to the H7N9 virus (Table S3). Although human populations that have not previously encountered H7N9 would likely see these pHLA1s as novel, there is also the possibility that there could be some "plasticity" in the cross-recognition of antigenic variants (15,16).…”

In vitro modeling of the interaction between human epithelial cells and lymphocytes upon influenza infection

“…Influenza virions infect the cells of respiratory pseudostratified columnar epithelium consisting of a single layer of three major cells types, namely ciliated, goblet, and Clara cells 2. Data from murine studies, along with limited human data, suggest that CD8 + cytotoxic T lymphocytes (CTL) that recognize conserved epitopes of structural influenza proteins are the main mediators of influenza virus clearance 3, 4, 5, 6, 7. Additionally, the fact that many CTLs recognize epitopes shared between different influenza strains offers the potential for broad cross‐strain immunity 8, 9, 10.…”