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The Presumed Hyporesponsive Behavior of Rheumatoid Arthritis T Lymphocytes Can Be Attributed to Spontaneous Ex Vivo Apoptosis rather than Defects in T Cell Receptor Signaling¹

Joana R. F. Abreu^*, Aleksander M. Grabiec^*, Sarah Krausz^*, René Spijker, Tomasz Burakowski, Wlodzimierz Maslinski, Eric Eldering, Paul P. Tak^* and Kris A. Reedquist^2,*

^* Division of Clinical Immunology and Rheumatology and Department of Experimental Immunology, Academic Medical Center, University of Amsterdam, The Netherlands; and Department of Pathophysiology and Immunology, Institute of Rheumatology, Warsaw, Poland

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-, and IFN-) 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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This research was supported by a Dutch Arthritis Association Grant (NR 05-2-103) to K.A.R.

² Address correspondence and reprint requests to Dr. Kris A. Reedquist, Division of Clinical Immunology and Rheumatology, Academic Medical Center, University of Amsterdam, Room K0-140, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands. E-mail address: k.a.reedquist{at}amc.uva.nl

³ Abbreviations used in this paper: RA, rheumatoid arthritis; SF, synovial fluid; FLS, fibroblast-like synoviocyte; PMA/I, PMA/ionomycin; HD, healthy donor; PB, peripheral blood; SFMC, SF mononuclear cell; PI, propidium iodide; RT-MLPA, reverse transcription multiplex ligation-dependent amplification.