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

Lookup NU author(s): Laura Ridgley, Dr Amy Anderson, Dr Nicola Maney, Najib Naamane, Andrew Skelton, Professor John Isaacs, Dr Arthur Pratt

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


Abstract

© 2019 Ridgley, Anderson, Maney, Naamane, Skelton, Lawson, Emery, Isaacs, Carmody and Pratt.Objective: We have previously shown that increased circulating interleukin-6 (IL-6) results in enhanced CD4+ T cell signaling via signal transduction and activator of transcription-3 (STAT3) in early rheumatoid arthritis (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 modeled naïve CD4+ T cell exposure to pathophysiological concentrations of IL-6 in vitro, assessing the dynamic transcriptional and functional consequences for downstream effector cells utilizing microarray and flow cytometry. Fresh blood from treatment-naïve early arthritis patients was phenotyped in parallel for comparison. Results: T cell sensitivity to IL-6 was most marked in the naïve subset, and related to gp130 rather than IL-6R expression. Exposure of healthy naïve 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 toward 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.


Publication metadata

Author(s): Ridgley LA, Anderson AE, Maney NJ, Naamane N, Skelton AJ, Lawson CA, Emery P, Isaacs JD, Carmody RJ, Pratt AG

Publication type: Article

Publication status: Published

Journal: Frontiers in Immunology

Year: 2019

Volume: 10

Online publication date: 03/07/2019

Acceptance date: 19/06/2019

Date deposited: 05/08/2019

ISSN (electronic): 1664-3224

Publisher: Frontiers Media S.A.

URL: https://doi.org/10.3389/fimmu.2019.01535

DOI: 10.3389/fimmu.2019.01535


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