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

Chris P Verschoor; Emilie Picard; Melissa K Andrew; Laura Haynes; Mark Loeb; Graham Pawelec; George A Kuchel

doi:10.3389/fragi.2022.1098200

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

Front Aging. 2023 Jan 5:3:1098200. doi: 10.3389/fragi.2022.1098200. eCollection 2022.

Authors

Chris P Verschoor^{1

2}, Emilie Picard¹, Melissa K Andrew³, Laura Haynes⁴, Mark Loeb⁵, Graham Pawelec^{1

6}, George A Kuchel⁴

Affiliations

¹ Health Sciences North Research Institute, Sudbury, ON, Canada.
² Northern Ontario School of Medicine, Sudbury, ON, Canada.
³ Department of Medicine, Dalhousie University, Halifax, NS, Canada.
⁴ UConn Center on Aging, University of Connecticut School of Medicine, Farmington, CT, United States.
⁵ Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON, Canada.
⁶ Department of Immunology, University of Tübingen, Tübingen, Germany.

Abstract

Granzymes are a family of serine-proteases that act as critical mediators in the cytolytic and immunomodulatory activities of immune cells such as CD8⁺ T-cells and natural killer (NK) cells. Previous work indicates that both granzyme B (GZB) and K (GZK) are increased with age in CD8⁺ T-cells, and in the case of GZB, contribute to dysfunctional immune processes observed in older adults. Here, we sought to determine how GZB and GZK expression in NK-cells, and CD4⁺, CD8⁺, and gamma-delta T-cells, quantified in terms of positive cell frequency and mean fluorescence intensity (MFI), differed with age, age-related health-traits and the antibody response to high-dose influenza vaccine. We found that the frequency and MFI of GZB-expressing NK-cells, and CD8⁺ and Vδ1+ T-cells, and GZK-expressing CD8⁺ T-cells was significantly higher in older (66-97 years old; n = 75) vs. younger (24-37 years old; n = 10) adults by up to 5-fold. There were no significant associations of GZB/GZK expression with sex, frailty or plasma levels of TNF or IL-6 in older adults, but those who were seropositive for cytomegalovirus (CMV) exhibited significantly higher frequencies of GZB+ NK-cells, and CD4⁺, CD8⁺ and Vδ1+ T-cells, and GZK+ CD8⁺ T-cells (Cohen's d = .5-1.5). Pre-vaccination frequencies of GZB+ NK-cells were positively correlated with vaccine antibody responses against A/H3N2 (d = .17), while the frequencies of GZK+ NK and CD8⁺ T-cells were inversely associated with A/H1N1 (d = -0.18 to -0.20). Interestingly, GZK+ NK-cell frequency was inversely correlated with pre-vaccination A/H1N1 antibody titres, as well as those measured over the previous 4 years, further supporting a role for this subset in influencing vaccine antibody-responses. These findings further our understanding of how granzyme expression in different lymphoid cell-types may change with age, while suggesting that they influence vaccine responsiveness in older adults.

Keywords: CMV; NK-cells; aging; granzyme B; granzyme K; influenza; t-cells; vaccination.