Investigation of CD4 and CD8 T cell-mediated protection against influenza A virus in a cohort study

Abstract

Background: The protective effect of T cell-mediated immunity against influenza virus infections in natural settings remains unclear, especially in seasonal epidemics.

Methods: To explore the potential of such protection, we analyzed the blood samples collected longitudinally in a community-based study and covered the first wave of pandemic H1N1 (pH1N1), two subsequent pH1N1 epidemics, and three seasonal H3N2 influenza A epidemics (H3N2) for which we measured pre-existing influenza virus-specific CD4 and CD8 T cell responses by intracellular IFN-γ staining assay for 965 whole blood samples.

Results: Based on logistic regression, we found that higher pre-existing influenza virus-specific CD4 and CD8 T cell responses were associated with lower infection odds for corresponding subtypes. Every fold increase in H3N2-specific CD4 and CD8 T cells was associated with 28% (95% CI 8%, 44%) and 26% (95% CI 8%, 41%) lower H3N2 infection odds, respectively. Every fold increase in pre-existing seasonal H1N1 influenza A virus (sH1N1)-specific CD4 and CD8 T cells was associated with 28% (95% CI 11%, 41%) and 22% (95% CI 8%, 33%) lower pH1N1 infection odds, respectively. We observed the same associations for individuals with pre-epidemic hemagglutination inhibition (HAI) titers < 40. There was no correlation between pre-existing influenza virus-specific CD4 and CD8 T cell response and HAI titer.

Conclusions: We demonstrated homosubtypic and cross-strain protection against influenza infections was associated with T cell response, especially CD4 T cell response. These protections were independent of the protection associated with HAI titer. Therefore, T cell response could be an assessment of individual and population immunity for future epidemics and pandemics, in addition to using HAI titer.

Keywords: Influenza; Susceptibility; T cell-mediated immunity.

Fig. 1

Timelines of our study and local influenza activity for pH1N1 (red) and H3N2 (blue) virus from 2009 to 2013. Shaded regions represented the period for the 10 rounds of serum collections (R1 to R10) and 4 rounds of whole blood collections (R1, R3, R5, and R7). The gray period indicated the rounds with CD4 and CD8 measurements. Arrows indicated the pre-existing CD4 and CD8 response and the corresponding epidemic

Fig. 2

The pre-existing CD4 responses among infected and uninfected individuals in the first pandemic wave of pH1N1 (A) and the five epidemics of pH1N1 (C, E) and H3N2 (B, D, F) in 2010–2013. Star indicates a statistically significant difference with a p-value < 0.05 by Wilcoxon the signed-rank test. The T cell response was measured using whole blood samples collected in R1, R3, R3, R5, R7, and R7 for A–F, respectively

Fig. 3

The pre-existing CD8 responses among infected and uninfected individuals in the first pandemic wave of pH1N1 (A) and the five epidemics of pH1N1 (C, E) and H3N2 (B, D, F) in 2010–2013. Star indicates a statistically significant difference with a p-value < 0.05 by the Wilcoxon signed-rank test. The T cell response was measured using whole blood samples collected in R1, R3, R3, R5, R7, and R7 for A–F, respectively

Fig. 4

Spearman correlation between pre-epidemic HAI titers and CD4 (A) or CD8 (B) T cell response

Fig. 5

The odds ratios for influenza virus infection for every fold increase in influenza subtype-specific CD4 (A) and CD8 (B) T cell response for sH1N1, pH1N1, and H3N2 estimated by logistic regression, adjusted for age groups, pre-epidemic HAI titer, and difference in infection risk for epidemics for pH1N1 (2009 pandemic, 2011 and 2013 epidemic) and H3N2 (2010, 2012, 2013 epidemic). Same analyses were also conducted in a subgroup of individuals with pre-epidemic HAI titer < 40

Fig. 6

The odds ratios for influenza virus infection for every fold increase in influenza subtype-specific CD4 (A) and CD8 (B) T cell response for sH1N1, pH1N1, and H3N2 estimated by logistic regression for children (age < 18) and adults (age ≥ 18), adjusted for pre-epidemic HAI titer and difference in infection risk for epidemics for pH1N1 (2009 pandemic, 2011 and 2013 epidemic) and H3N2 (2010, 2012, 2013 epidemic). Arrow in confidence intervals indicates that the upper bound was higher than 2 (which is the limit of the x-axis)