IL-6 mediated transcriptional programming of CD4+ T cells in early rheumatoid arthritis

We hypothesised that sustained exposure of naïve CD4+ T cells to IL-6 might imprint them with a distinct transcriptional programme, whose molecular and functional consequences following subsequent TCR ligation was relevant to disease development. Preexposure of healthy naïve CD4+ T-cells to pathophysiological levels of the cytokine caused induction of STAT3 target genes known to discriminate RA patients from disease controls in the clinic. After TCR stimulation IL-6 pre-exposed cells exhibited enhanced proliferative capacity, activation and a propensity towards Th1 differentiation, compared to non-exposed cells. Naïve or memory CD4+ T-cells were isolated from 3 healthy donors and cultured with 0.5ng/ml IL-6 and equimolar sIL-6R for 72 hours prior to washing and stimulation with 0.2μg/ml anti-CD3 and 1μg/ml for 6 days. anti-CD28 for 4 hours. RNA was extracted for global gene expression analysis at baseline (t0), after 6 hours or 72 hours exposure to IL-6 (t1,t2) and 4 hours post-TCR stimulation (t3)