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Cited by 27Rheumatoid Arthritis Research and TherapiesCytokine Signaling Pathways and InteractionsT-cell and B-cell Immunology

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

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Ridgley, Laura A., Anderson, Amy E., Maney, Nicola J., Naamane, Najib, Skelton, Andrew J., Lawson, Catherine A., Emery, Paul, Isaacs, John D. +2 more·2019·Frontiers in Immunology
DOI 10.3389/fimmu.2019.01535PMC PMC6618050
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Abstract

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 naïve 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-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 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.

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  • IL-6 receptor expression varies significantly among different T cell populations and environmental contexts.

    “IL-6 receptor expression varies significantly among different T cell populations and environmental contexts”

    From CDK8 fine-tunes IL-6 transcriptional activities by limiting STAT3 resident time at the gene loci (2020) · cites this paper as Ridgley et al., 2019

    The Results section reports significantly different surface IL-6R expression among naïve, central-memory, and effector-memory CD4+ T cells, with the highest expression on central-memory cells. The paper discusses how conditions affect IL-6 responses, but the passages do not show that environmental context changes receptor expression. Page numbers were not provided. (LLM, conf=0.86)

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Authors
Ridgley, L. A., Anderson, A. E., Maney, N. J., Naamane, N., Skelton, A. J., Lawson, C. A., Emery, P., Isaacs, J. D., Carmody, R. J., & Pratt, A. G.
Affiliations
  • Newcastle University (GB)
  • University of Leeds (GB)
  • Newcastle upon Tyne Hospitals NHS Foundation Trust (GB)
Corresponding author
Pratt, Arthur G.
ORCID
Venue
Frontiers in Immunology
Publisher
Frontiers Media SA
Published
2019-07-03
Volume
10
Pages
1535-1535
ISSN
1664-3224 (ISSN-L)
DOI
10.3389/fimmu.2019.01535
PMC
PMC6618050
OpenAlex
W2953411401
Cited by
27
References
36
Citations by year
2026: 2 · 2025: 5 · 2024: 2 · 2023: 3 · 2022: 5 · 2021: 6 · 2020: 3 · 2019: 1
FWCI
2.85
Type
journal article
Language
en
Open access
Licence
Locations
  • Frontiers in Immunology (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • White Rose Research Online (University of Leeds, The University of Sheffield, University of York) (acceptedVersion)
  • St George's Online Research Archive (St George's University of London) (acceptedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Newcastle University ePrints (Newcastle Univesity) (cc-by)
Funders
  • National Institute for Health and Care Research (NIHR200224, CL-2011-01-002)
  • British Medical Association
  • Newcastle University
  • Versus Arthritis
  • Medical Research Council (MR/P020941/1)
  • NIHR Newcastle Biomedical Research Centre
  • Leeds Biomedical Research Centre
Topics
  • Health Sciences › Medicine › Rheumatology › Rheumatoid Arthritis Research and Therapies
  • Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
  • Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
Keywords
interleukin-6, rheumatoid arthritis, naive CD4+ T cells, STAT3 signaling, gp130, transcriptional programming, Th1 differentiation, T cell proliferation, T cell activation, T cell receptor stimulation, early arthritis, immune dysregulation
MeSH terms
Adult, Aged, Aged, 80 and over, Arthritis, Rheumatoid, Female, Humans, Male, Middle Aged, Receptors, Antigen, T-Cell, Transcription, Genetic, Signal Transduction, CD4-Positive T-Lymphocytes, Interleukin-6, Models, Immunological, STAT3 Transcription Factor

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