Nicotine Changes the microRNA Profile to Regulate the FOXO Memory Program of CD8⁺ T Cells in Rheumatoid Arthritis

Area of Science:

• Immunology
• Epigenetics

Background:

• Smoking is known to suppress PD-1 expression in rheumatoid arthritis (RA) patients.
• The epigenetic mechanisms underlying smoking's effect on T cell memory, particularly in RA, remain unclear.

Purpose of the Study:

• To investigate if smoking influences CD8+ T cell memory formation through a microRNA (miR)-dependent epigenetic mechanism.
• To explore the role of specific miRs and the FOXO signaling pathway in smoking-associated T cell changes.

Main Methods:

• Flow cytometry was used to analyze CD8+ T cell phenotypes in smokers and non-smokers, including RA patients and healthy controls.
• Microarray analysis identified differentially expressed miRs, followed by in vitro nicotine stimulation of CD8+ T cells to assess miR and gene transcription via qPCR.
• Bioinformatic predictions identified target proteins within the FOXO signaling pathway for differentially expressed miRs.

Main Results:

• Smokers showed a higher frequency of CD27+CD107a-CD8+ T cells, a naive-memory phenotype, with low PD-1 expression.
• Eight miRs were differentially expressed in smokers' CD8+ T cells, including upregulated let-7 family members, miR-92a-3p, miR-150-5p, and miR-181-5p.
• In vitro nicotine exposure induced miR-150-5p and miR-181a-5p in naive-memory CD8+ T cells and altered the mRNA/miR ratio within the FOXO pathway.

Conclusions:

• Smokers exhibit an increased prevalence of CD8+ T cells with a naive-memory phenotype.
• These cells possess a unique miR expression profile that interacts with the FOXO pathway, suggesting a novel epigenetic mechanism for altered T cell memory in smokers.