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

## TL;DR

This study explores how different types of naïve CD8+ T cells change with age and identifies NTN cells as the most true naïve type.

## Contribution

The study reveals distinct functional and phenotypic differences among naïve CD8+ T cell subsets, particularly highlighting NTN cells.

## Key findings

- NCD27 and NTN cells show low differentiation markers and high mitochondrial fitness.
- Age-related changes are less pronounced in NCD27 and NTN cells compared to other subsets.
- Hierarchical clustering separates naïve CD8+ T cells into two distinct groups based on marker expression.

## 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.