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

Smoking suppresses PD-1 expression in patients with rheumatoid arthritis (RA). In this study, we assess if smoking changed the epigenetic control over CD8 T cell memory formation through a microRNA (miR) dependent mechanism. Phenotypes of CD8 T cells from smokers and non-smokers, RA and healthy, were analyzed by flow cytometry. A microarray analysis was used to screen for differences in miR expression. Sorted CD8 cells were stimulated with nicotine and analyzed for transcription of miRs and genes related to memory programming by qPCR. CD27CD107aCD8 T cells, defining a naïve-memory population, had low expression of PD-1. Additionally, the CD27 population was more frequent in smokers ( = 0.0089). Smokers were recognized by differential expression of eight miRs. Let-7c-5p, let-7d-5p and let-7e-5p, miR-92a-3p, miR-150-5p, and miR-181-5p were up regulated, while miR-3196 and miR-4723-5p were down regulated. These miRs were predicted to target proteins within the FOXO-signaling pathway involved in CD8 memory programming. Furthermore, miR-92a-3p was differentially expressed in CD8 cells with naïve-memory predominance. Nicotine exposure of CD8 cells induced the expression of miR-150-5p and miR-181a-5p in the naïve-memory cells . Additionally, nicotine exposure inverted the ratio between mRNAs of proteins in the FOXO pathway and their targeting miRs. Smokers have a high prevalence of CD8 T cells with a naïve-memory phenotype. These cells express a miR profile that interacts with the memory programming conducted through the FOXO pathway.