Association Between Immunosuppressive Cell Populations and Immune Response to Influenza Vaccination in Younger and Older Adults

Background: Seasonal influenza vaccination shows highly variable effectiveness across individuals, particularly in older adults, in whom age-related immune decline compromises protective responses. Methods: This study evaluated immune responses to the 2019/2020 quadrivalent influenza vaccine in 75 individuals aged 25–89 years. Influenza-specific antibody titers and virus-neutralizing activity were measured before and four weeks after vaccination, and participants were stratified as high or low responders. Results: We observed that older individuals exhibited increased frequencies of myeloid-derived suppressor cells (MDSCs) and activated regulatory T cells (Treg) expressing HLA-DR and CD38, consistent with enhanced immunosuppressive activity. Importantly, higher levels of these immunoregulatory populations correlated with poor vaccine responsiveness in both adult and older participants. Additionally, circulating T follicular regulatory (Tfr) cells were elevated in older participants and in low responders, whereas T follicular helper (Tfh) cells remained unchanged, resulting in an increased Tfr/Tfh ratio associated with impaired antibody production. However, when adjusting for possible confounders, most immunoregulatory subsets did not remain independently associated with responder status, except CD38+ Treg cells. Conclusions: These findings suggest that immunoregulatory networks, while essential for controlling chronic inflammation during aging, may limit vaccine-induced immunity. Identifying biomarkers such as MDSC frequency, activated Treg phenotype, and Tfr/Tfh balance may contribute to the identification of individuals with different levels of vaccine responsiveness and could help inform future personalized vaccination strategies.