IL-6 Mediated Transcriptional Programming of Naïve CD4+ T Cells in Early Rheumatoid Arthritis Drives Dysregulated Effector Function

Objective: We have previously shown that increased circulating interleukin-6 (IL-6) results in enhanced CD4+ T-cell signalling via signal transduction and activator of transcription-3 (STAT3) in early RA. We tested the hypothesis that transcriptional “imprinting” of T-cells by this mechanism skews downstream effector responses, reinforcing immune dysregulation at a critical, but targetable, disease phase. Methods: We modelled naive CD4+ T cell exposure to pathophysiological concentrations of IL-6 in vitro, assessing the dynamic transcriptional and functional consequences for downstream effector cells utilising microarray and flow cytometry. Fresh blood from treatment-naive early arthritis patients was phenotyped in parallel for comparison. Results: T-cell sensitivity to IL-6 was most marked in the naive subset, and related to gp130 rather than IL-6R expression. Exposure of healthy naive CD4+ T-cells to IL-6 induced the same STAT3 target genes as previously seen to discriminate RA patients from disease controls. After TCR stimulation IL-6 pre-exposed cells exhibited enhanced proliferative capacity, activation and a propensity towards Th1 differentiation, compared to non-exposed cells. An entirely analogous phenotype was observed in early RA compared to control CD4+ T-cells. Conclusions: Sustained IL-6 exposure at a critical point in the natural history of RA “primes” the adaptive immune system to respond aberrantly to TCR stimulation, potentiating disease induction with implications for the optimal timing of targeted therapy.