T-cell responses following Natural Influenza Infection or Vaccination in Solid Organ Transplant Recipients

Abstract

Little is known about cell-mediated immune responses to natural influenza infection in solid organ transplant (SOT) patients. The aim of our study was to evaluate the CD4⁺ and CD8⁺ responses to influenza A and B infection in a cohort of SOT patients. We collected peripheral blood mononuclear cells at influenza diagnosis and four weeks later from 31 SOT patients during the 2017-2018 influenza season. Infection-elicited influenza-specific CD4⁺ and CD8⁺ T-cell responses were measured using flow cytometry and intracellular cytokine staining and compared to responses following influenza vaccine in SOT patients. Natural infection was associated with a significant increase in CD4⁺ T-cell responses. For example, polyfunctional cells increased from 21 to 782 and from 193 to 1436 cells per 10⁶ CD4⁺ T-cells among influenza A/H3N2 and B-infected patients (p = 0.006 and 0.004 respectively). Moreover, infection-elicited CD4⁺ responses were superior than vaccine-elicited responses for influenza A/H1N1 (931 vs 1; p = 0.026), A/H3N2 (647 vs 1; p = 0.041) and B (619 vs 1; p = 0.004). Natural influenza infection triggers a significant increase in CD4⁺ T-cell responses in SOT patients. Infection elicits significantly stronger CD4⁺ responses compared to the influenza vaccine and thereby likely elicits better protection against reinfection.

Figure 1

Evaluation of influenza-specific CD4⁺ and CD8⁺ T-cell immunity among influenza A/H3N2- and influenza B-infected patients at influenza diagnosis and Day 28. IFN-γ: interferon-γ; TNF-α: tumor-necrosis factor-α; IL: interleukin. Results were expressed as number of cytokine-producing CD4⁺ cells/10⁶ CD4⁺ T-cells or CD8⁺ cells/10⁶ CD8⁺ T-cells. For data presentation, cell frequencies labelled as TNFα⁺, IFNγ⁺, IL2⁺ or IL4⁺ were cells producing the given cytokine, regardless of the production of other cytokines. The upper edge of the box represents the median value, and the error bars represent the interquartile range. Red and blue dots represent individual patient frequencies at influenza diagnosis and Day 28, respectively.

Figure 2

Evaluation of heterosubtypic influenza A/H1N1-specific CD4⁺ and CD8⁺ T-cell immunity among influenza A/H3N2-infected patients IFN-γ: interferon-γ; TNF-α: tumor-necrosis factor-α; IL: interleukin. Results were expressed as number of cytokine-producing CD4⁺ cells/10⁶ CD4⁺ T-cells or CD8⁺ cells/10⁶ CD8⁺ T-cells. For data presentation, cell frequencies labelled as TNFα⁺, IFNγ⁺, IL2⁺ or IL4⁺ were cells producing the given cytokine, regardless of the production of other cytokines. The upper edge of the box represents the median value, and the error bars represent the interquartile range. Black and green dots represent individual frequencies in influenza A/H3N2-infected patients at influenza diagnosis and Day 28, respectively.

Figure 3

Comparison of median number of influenza-specific infection-elicited and vaccine-elicited cytokine-producing CD4⁺ and CD8⁺ T-cells in SOT recipients. SOT: Solid organ transplant; IFN-γ: interferon-γ; TNF-α: tumor-necrosis factor-α; IL: interleukin. Results were expressed as number of vaccine-elicited cytokine-producing CD4⁺ cells/10⁶ CD4⁺ T-cells and number of cytokine-producing CD8⁺ cells/10⁶ CD8⁺ T-cells. For data presentation, cell frequencies labelled as TNFα⁺, IFNγ⁺, IL2⁺ or IL4⁺ were cells producing the given cytokine, regardless of the production of other cytokines. The boxes represents the median value. Pre-vaccination frequencies were subtracted from post-vaccination frequencies to highlight vaccine-elicited responses, whereas frequencies at influenza diagnosis were subtracted from frequencies at Day 28 to highlight infection-elicited responses.