The presumed hyporesponsive behavior of rheumatoid arthritis T lymphocytes can be attributed to spontaneous ex vivo apoptosis rather than defects in T cell receptor signaling

Joana R F Abreu, Aleksander M. Grabiec, Sarah Krausz, René Spijker, Tomasz Burakowski, Wlodzimierz Maslinski, Eric Eldering, Paul P. Tak, Kris A. Reedquist

    Research output: Contribution to journalArticlepeer-review

    Abstract

    Genetic associations and the clinical success of compounds targeting TCR costimulatory proteins suggest an active role for TCR signaling in the initiation and perpetuation of rheumatoid arthritis (RA). Paradoxically, T cells isolated from affected joints in RA show impaired proliferative and cytokine responses following stimulation with mitogens and recall Ags attributed in part to chronic T cell exposure to oxidative stress and inflammatory cytokines. Therefore, it is uncertain how local autoreactive TCR signaling contributes to pathology in established RA. Using single-cell analysis, we show that in contrast to results obtained in bulk culture assays, T cells from the synovial fluid of RA patients proliferate and produce cytokines (IL-2, TNF-α, and IFN-γ) as efficiently, if not more so, than T cells isolated from healthy donors and RA patient peripheral blood following TCR/CD28 stimulation. RA synovial fluid T cell hyporesponsiveness observed in bulk cultures can be attributed to spontaneous apoptosis ex vivo, which is associated with altered ratios of proapoptotic Noxa and anti-apoptotic Mcl-1 expression. The absence of RA synovial T cell proliferation and cytokine production in situ, despite the capacity of these cells to support productive TCR signaling, suggests that T cells contribute to local pathology in established RA by TCR-independent mechanisms. Copyright © 2009 by The American Association of Immunologists, Inc.
    Original languageEnglish
    Pages (from-to)621-630
    Number of pages9
    JournalJournal of Immunology
    Volume183
    Issue number1
    DOIs
    Publication statusPublished - 1 Jul 2009

    Keywords

    • 80 and over
    • Adult
    • Aged
    • Antigen
    • Apoptosis
    • Apoptosis: immunology
    • Arthritis
    • Cell Proliferation
    • Cells
    • Cultured
    • Female
    • Humans
    • Male
    • Middle Aged
    • Receptors
    • Rheumatoid
    • Rheumatoid: immunology
    • Rheumatoid: metabolism
    • Rheumatoid: pathology
    • Signal Transduction
    • Signal Transduction: immunology
    • Synovial Fluid
    • Synovial Fluid: immunology
    • Synovial Fluid: metabolism
    • T-Cell
    • T-Cell: deficiency
    • T-Cell: physiology
    • T-Lymphocyte Subsets
    • T-Lymphocyte Subsets: immunology
    • T-Lymphocyte Subsets: metabolism
    • T-Lymphocyte Subsets: pathology

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