Phenotypic and functional heterogeneity of naïve CD8+ T cells in human peripheral blood during aging

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, N CCR7 (CD45RA + CCR7 + ), N CD28 (CD45RA + CD28 + ), N CD27 (CD45RA + CD27 + ), and phenotypically most “true-naïve”-like, N TN (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. N CD27 and N TN 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 N CD27 and N TN , with lower expression of differentiation markers and pro-inflammatory molecules, and cluster 2, including N CCR7 and N CD28 cells, in which these parameters were more expressed. Age-related changes were observed in all subsets, although they were less pronounced for the N CD27 and N TN subsets. Taken together, this study demonstrates significant heterogeneity among naïve CD8 + T cell subsets, with N TN cells representing the most bona fide naïve phenotype and N CD27 showing a partially similar phenotype. These findings significantly enhance our understanding of naïve CD8 + T cell biology and function.