Cevirgel, AlperVos, MartijnBijvank, Elskevan Beek, Josinevan der Heiden, MariekeBuisman, Anne-Marievan Baarle, Debbie2025-03-122025-03-122025-03-084005579010.1186/s12979-025-00504-0https://rivm.openrepository.com/handle/10029/632133The T cell compartment undergoes significant age-related changes, contributing to the decline of the adaptive immune system and increasing the risk of suboptimal antibody responses to vaccines in older adults. To better understand the association between T cell phenotypes and vaccine responsiveness, we conducted an in-depth analysis of CD4+, CD8+, and γδ + T cells on VITAL cohort participants who are low or high responders to multiple vaccines (influenza, pneumococcal, and SARS-CoV-2).Using spectral cytometry and FlowSOM, we identified detailed phenotypes of naïve, regulatory, and terminally differentiated T cells. We observed that the percentages of CD31 + naïve CD4+, CD31 + naïve CD8+, and CD38 + naïve CD8 + T cells were significantly lower in low vaccine responders. Notably, CD31 + naïve T cell subsets showed a stronger correlation with immune entropy, a measure of cumulative immune system perturbations, than with age itself.These findings suggest that subsets of naïve cells could be associated with weak vaccine responsiveness and immunosenescence. Furthermore, these naive T cell signatures could help predict weak vaccine responses, potentially informing targeted vaccination strategies in older adults.EudraCT: 2019-000836-24.en© 2025. The Author(s).Journal ArticleImmun Ageing 2025; 22(1):1010.1186/s12979-025-00504-0