Multi-Omics Analysis of Human Blood Cells Reveals Unique Features of Age-Associated Type 2 CD8 Memory T Cells.

A unique population of memory CD8 T cells lacking CXCR3 with Th2-like cytokine production accumulates with age in human peripheral blood.

• Human PBMCs from healthy donors aged 20-82 years were analyzed using a 36-color spectral flow cytometry panel focused on T cells.
• These cells were identified as CXCR3-negative central memory CD8 T cells.
• The cells produce Th2-like cytokines, distinguishing them from typical CD8 T cell effector responses.
• The population was termed 'age-associated type 2 CD8 memory T cells' based on their phenotype and accumulation pattern.

Naïve CD8 T cells show an age-dependent bias toward Th2 cytokine production accompanied by transcriptional and epigenetic changes.

• The Th2 cytokine production bias was observed in naïve CD8 T cells from older donors.
• Transcriptional changes supporting the Th2-like phenotype were identified in naïve CD8 T cells.
• Epigenetic changes were also found to support this Th2-like phenotype in naïve CD8 T cells.
• The findings support a model of age-dependent drift in epigenetic regulation toward a Th2-like phenotype.

Accumulation of CXCR3-negative central memory CD8 T cells was associated with specific health conditions including asthma, chronic liver conditions, and type 2 diabetes.

• Health outcome association analysis was performed to link immune cell population changes to disease states.
• Three distinct conditions were associated: asthma, chronic liver conditions, and type 2 diabetes.
• The association was specifically with the CXCR3-negative central memory CD8 T cell population.
• These associations suggest a pathogenic role for the age-associated Th2-like CD8 T cell population.

The study utilized multi-omics approaches including spectral flow cytometry, transcriptomics, and epigenetics to characterize age-related immune changes.

• A 36-color spectral flow cytometry panel focused on T cells was employed.
• The cohort consisted of healthy donors spanning ages 20-82 years.
• Peripheral blood mononuclear cells (PBMCs) were the primary sample type analyzed.
• Multi-omics analysis integrated flow cytometry, transcriptional, and epigenetic data to characterize the age-associated population.

The results support a model in which age-dependent epigenetic drift toward a Th2-like phenotype drives the emergence of a pathogenic Th2-like immune population.

• Epigenetic changes were identified as a key mechanism underlying the age-associated Th2 bias in CD8 T cells.
• The model proposes that epigenetic drift precedes and drives the phenotypic changes observed in both naïve and memory CD8 T cell compartments.
• The pathogenic nature of these cells is supported by their association with asthma, chronic liver conditions, and type 2 diabetes.
• The drift was characterized as an age-dependent process affecting CD8 T cell identity and cytokine production capacity.