Diverse Heterologous Primary Infections Radically Alter Immunodominance Hierarchies and Clinical Outcomes Following H7N9 Influenza Challenge in Mice

Abstract

The recent emergence of a novel H7N9 influenza A virus (IAV) causing severe human infections in China raises concerns about a possible pandemic. The lack of pre-existing neutralizing antibodies in the broader population highlights the potential protective role of IAV-specific CD8+ cytotoxic T lymphocyte (CTL) memory specific for epitopes conserved between H7N9 and previously encountered IAVs. In the present study, the heterosubtypic immunity generated by prior H9N2 or H1N1 infections significantly, but variably, reduced morbidity and mortality, pulmonary virus load and time to clearance in mice challenged with the H7N9 virus. In all cases, the recall of established CTL memory was characterized by earlier, greater airway infiltration of effectors targeting the conserved or cross-reactive H7N9 IAV peptides; though, depending on the priming IAV, each case was accompanied by distinct CTL epitope immunodominance hierarchies for the prominent KbPB1703, DbPA224, and DbNP366 epitopes. While the presence of conserved, variable, or cross-reactive epitopes between the priming H9N2 and H1N1 and the challenge H7N9 IAVs clearly influenced any change in the immunodominance hierarchy, the changing patterns were not tied solely to epitope conservation. Furthermore, the total size of the IAV-specific memory CTL pool after priming was a better predictor of favorable outcomes than the extent of epitope conservation or secondary CTL expansion. Modifying the size of the memory CTL pool significantly altered its subsequent protective efficacy on disease severity or virus clearance, confirming the important role of heterologous priming. These findings establish that both the protective efficacy of heterosubtypic immunity and CTL immunodominance hierarchies are reflective of the immunological history of the host, a finding that has implications for understanding human CTL responses and the rational design of CTL-mediated vaccines.

Memory T Cell Dynamics in the Lung during Influenza Virus Infection

“…Both memory CD4 + and CD8 + T cells are able to protect mice from a lethal IAV infection in the absence of any other immune cell population (14,23,85), and the size of the memory T cell compartment is a good correlate of protection against a secondary heterologous infection (86,87). In humans, survival from a new influenza strain depends on the presence of memory CD8 + T cells (17,18), and in a rechallenge study, the numbers of CD4 + T cells directed against internal proteins correlated with lower viral titers and weaker symptoms (17).…”

Innate and adaptive T cells in influenza disease

“…When mice that have recovered from a primary influenza infection are re-infected with a heterologous IAV (a strain with different surface glycoproteins but the same internal proteins) that is resistant to neutralization by antibody induced by the primary infection, influenzaspecific CD8 + T cells are responsible for accelerated viral clearance and reduced disease burden [13,[59][60][61]. Studies in guinea pigs also demonstrated that priming with the 2009 pandemic H1N1 virus confers protection against the 2013 avian H7N9 IAV [62].…”

CD4 T cells in protection from influenza virus: Viral antigen specificity and functional potential

“…Dramatic shifts in the immunodominance hierarchy upon heterosubtypic infection have also been observed for CD8 T cells. [71][72][73] Previously activated CD4 T cells are known to require lower epitope density to become reactivated and also to expand more rapidly than naive CD4 T cells. [74][75][76][77] Our later studies showed that the advantage that is afforded to memory CD4 T cells specific for internal virion proteins, at the expense of CD4 T cells specific for HA, could be overcome by an intermediate boost with HA-derived peptides derived from the second virus.…”