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Single-cell gene expression and TCR profiling reveal age-related differences in recent thymic emigrants

ABSTRACT: Following thymic egress, CD8+ T cells must undergo a post-thymic maturation process to transition from a recent thymic emigrant (RTE) to a mature naïve T cell. Since neonatal animals are comprised of significantly more RTEs, there is a prevailing notion that neonatal CD8+ T cells behave differently than their adult counterparts simply because they have undergone less post-thymic maturation. To test this theory, we leveraged a fate mapping mouse model and single cell sequencing to compare neonatal and adult CD8+ RTEs that have undergone that same amount of post-thymic maturation. Interestingly, we found neonatal and adult CD8+ RTEs exhibit distinct phenotypes, gene expression profiles, TCR usage and functions. These data suggest that neonatal CD8+ T cells are not simply ‘young’ adult CD8+ T cells and that age-related changes in CD8+ T cell functions in early life cannot be solely attributed to differences in the amounts of post-thymic maturation.

ORGANISM(S): Mus musculus

PROVIDER: GSE288766 | GEO | 2026/04/27

REPOSITORIES: GEO

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Project description:To understand better the nature of the poor response of human neonates to intracellular pathogens, we evaluated the transcriptome of neonates as compared to adult naÃ¯ve CD8-T cells. A specific transcription signature of the neonatal cells was found, characterized by a lower expression of signalling and CTL functional genes and a high expression of maturation, cell cycle and innate-immunity associated genes. Functional assays demonstrated that neonatal CD8-T cells undergo homeostatic proliferation, transcribe antimicrobial peptides and produce reactive oxygen species. Master transcription factors were found presumably responsible for this specific signature. Genome wide epigenetic studies showed a corresponding chromatin signature for a number of the differentially expressed genes. Altogether our results show that CD8 neonatal T cells have a particular genetic program with functions within the innate immune response, while still undergoing their maturation process. Neonates are highly susceptible to infections by intracellular pathogens, which are a major cause of infant morbidity and mortality. CD8-T cells control intracellular pathogens through cytotoxic mechanisms in an antigen-dependent manner. We found that human neonatal CD8-T cells, as compared to adult lymphocytes, had a distinctive pattern of gene transcription, characterized by the lower expression of genes involved in TCR signalling and cytotoxicity and a high expression of genes involved in cell cycle and innate immunity. Functional studies corroborated that neonatal CD8-T cells are less cytotoxic, transcribe antimicrobial peptides and produce reactive oxygen species. These properties could explain the high sensitivity of neonates to intracellular pathogen infections and outline novel functions of neonatal CD8-T cells. PBMC total RNAs from Adult and Neonate subjects were profiled after hybridization with Agilent SurePrint G3 Human GE 8x60K Microarray. CD8-T cells mRNA were extracted from 8 samples including: 4 Adults and 4 Neonates.

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Single-cell gene expression and TCR profiling reveal age-related differences in recent thymic emigrants

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