Markers of systemic inflammation are positively associated with influenza vaccine antibody responses with a possible role for ILT2(+)CD57(+) NK-cells

Abstract

Background With increasing age, overall health declines while systemic levels of inflammatory mediators tend to increase. Although the underlying mechanisms are poorly understood, there is a wealth of data suggesting that this so-called “inflammaging” contributes to the risk of adverse outcomes in older adults. We sought to determine whether markers of systemic inflammation were associated with antibody responses to the seasonal influenza vaccine. Results Over four seasons, hemagglutination inhibition antibody titres and ex vivo bulk peripheral blood mononuclear cell (PBMC) responses to live influenza viruses assessed via interferon (IFN)-γ/interleukin (IL)-10 production, were measured pre- and 4-weeks post-vaccination in young adults (n = 79) and older adults randomized to standard- or high-dose inactivated vaccine (n = 612). Circulating tumour necrosis factor (TNF), interleukin (IL)-6 and C-reactive protein (CRP) were also measured pre-vaccination. Post-vaccination antibody titres were significantly associated with systemic inflammatory levels; specifically, IL-6 was positively associated with A/H3N2 titres in young adults (Cohen’s d = 0.36), and in older high-dose, but not standard-dose recipients, all systemic inflammatory mediators were positively associated with A/H1N1, A/H3N2 and B titres (d = 0.10–0.45). We further show that the frequency of ILT2(+)CD57(+) CD56-Dim natural killer (NK)-cells was positively associated with both plasma IL-6 and post-vaccination A/H3N2 titres in a follow-up cohort of older high-dose recipients (n = 63). Pathway analysis suggested that ILT2(+)CD57(+) Dim NK-cells mediated 40% of the association between IL-6 and A/H3N2 titres, which may be related to underlying participant frailty. Conclusions In summary, our data suggest a complex relationship amongst influenza vaccine responses, systemic inflammation and NK-cell phenotype in older adults, which depends heavily on age, vaccine dose and possibly overall health status. While our results suggest that “inflammaging” may increase vaccine immunogenicity in older adults, it is yet to be determined whether this enhancement contributes to improved protection against influenza disease.

NK- and T-cell granzyme B and K expression correlates with age, CMV infection and influenza vaccine-induced antibody titres in older adults

“…While novel, these findings also represent a limitation of our study as we were unable to determine the mechanistic basis for this relationship or elucidate the phenotype of these cell types beyond their parental lineage; in fact, there may even be a relevant role for the aging-and CMV-related CD56-negative NK-cell subset, which we were unable to identify (Müller-Durovic et al, 2019). An exploratory analysis using immunophenotyping data published as part of a previous study (Picard et al, 2022) showed that the frequency of GZK+ NK-cells most strongly correlated with the frequency of CD56 dim NKG2A + NKG2C + NK-cells (d = .41; data not shown), which suggest a developmentally intermediate (i.e., from CD56 bright GZK + to CD56 dim GZK − NK-cells) or even tissue-resident phenotype (Yang et al, 2019;Melsen et al, 2022). Interestingly, we found that two markers of lymph node NK-cells, NKp46 and NKp30 (Eissens et al, 2012;Dogra et al, 2020), were also inversely correlated with A/H1N1 antibody responses in that previous study (Picard et al, 2022).…”

“…Although NK-and CD8 + T-cells are most often associated with the cytolytic response to respiratory infection, previous studies suggest that they are also important for vaccine-induced antibody responses to antigens from influenza (Herrero-Fernández et al, 2019;Picard et al, 2022) and other pathogens (Kalia et al, 2021). Given this, we sought to determine whether cell-specific granzyme expression was associated with hemagglutination inhibition (HAI) antibody titres prior to and following seasonal high-dose vaccination in our older adult participants.…”

“…An exploratory analysis using immunophenotyping data published as part of a previous study (Picard et al, 2022) showed that the frequency of GZK+ NK-cells most strongly correlated with the frequency of CD56 dim NKG2A + NKG2C + NK-cells (d = .41; data not shown), which suggest a developmentally intermediate (i.e., from CD56 bright GZK + to CD56 dim GZK − NK-cells) or even tissue-resident phenotype (Yang et al, 2019;Melsen et al, 2022). Interestingly, we found that two markers of lymph node NK-cells, NKp46 and NKp30 (Eissens et al, 2012;Dogra et al, 2020), were also inversely correlated with A/H1N1 antibody responses in that previous study (Picard et al, 2022). Considering that these markers, as well as NKG2A and NKG2C, are expressed on many other NK-cell subsets, a combined analysis of cellular phenotype and GZK expression would strengthen our current findings, especially if performed in the 4 years of our previously completed randomized vaccine trial.…”

“…TNF and IL-6 were quantified in participant plasma prevaccination using the Ella Automated Immunoassay System and Simple Plex 2nd generation Human TNF and IL-6 cartridges (R&D Systems, MN, United States); this has been previously described (Picard et al, 2022). CMV serostatus was determined in serum using a CMV IgG ELISA kit (Genesis Diagnostics Ltd., Littleport, United Kingdom) according to the manufacturer's instructions.…”

Emerging cellular senescence-centric understanding of immunological aging and its potential modulation through dietary bioactive components

“…It is prudent to consider here that the significance of compromised functions of the immune system during aging in augmenting organismal risk of infections and delayed immune response appears contentious. On one hand, there is mounting evidence that age-dependent functional and phenotypic changes in immune cells can contribute to reduced vaccine response and increased risk of infections during aging (He et al 2021 ; Loyer et al 2022 ; Sabbatinelli et al 2022 ; Simmons et al 2022 ); on the other hand, there are also reports indicating that aspects of immunosenescence, such as inflamm-aging, could be positively corelated with increased vaccine immunogenicity in older adults (Picard et al 2022 ). These conflicting observations corroborate the recent efforts of Pawelec et al that highlighted the limitations and lacunae of the prevailing one-dimensional view of immunosenescence (Pawelec et al 2020 ).…”