AUTHOR=Pangrazzi Luca , Pehl Patrizia , Hoffmann Lotti , Bachmann Martin , Chelini Gabriele , Keller Michael , Jenewein Brigitte , Cavinato Maria , Weinberger Birgit 
  
TITLE=Phenotypic and functional heterogeneity of naïve CD8+ T cells in human peripheral blood during aging
  
JOURNAL=Frontiers in Aging
  
VOLUME=Volume 7 - 2026
  
YEAR=2026
  
URL=https://www.frontiersin.org/journals/aging/articles/10.3389/fragi.2026.1765665
  
DOI=10.3389/fragi.2026.1765665
  
ISSN=2673-6217
  
ABSTRACT=Naïve CD8+ T cells are key players of adaptive immunity, but their heterogeneity and age-related changes are not fully understood. This study aimed to compare naïve CD8+ T cell subsets defined by different combinations of markers, namely, NCCR7 (CD45RA+CCR7+), NCD28 (CD45RA+CD28+), NCD27 (CD45RA+CD27+), and phenotypically most “true-naïve”-like, NTN (CD45RA+CCR7+CD28+CD27+CD57−). Peripheral blood was harvested from donors of various ages and the phenotype of the four subsets of naïve CD8+ T cells was analyzed. NCD27 and NTN cells showed similar phenotypes with low expression of differentiation markers, pro-inflammatory cytokines, and effector molecules. Furthermore, they exhibited optimal mitochondrial fitness, low senescence markers, reduced apoptosis, and high proliferation potential. Hierarchical clustering identified cluster one including NCD27 and NTN, with lower expression of differentiation markers and pro-inflammatory molecules, and cluster 2, including NCCR7 and NCD28 cells, in which these parameters were more expressed. Age-related changes were observed in all subsets, although they were less pronounced for the NCD27 and NTN subsets. Taken together, this study demonstrates significant heterogeneity among naïve CD8+ T cell subsets, with NTN cells representing the most bona fide naïve phenotype and NCD27 showing a partially similar phenotype. These findings significantly enhance our understanding of naïve CD8+ T cell biology and function.