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This Article Full Text (PDF) All Versions of this Article: jimmunol.0803278v1 183/1/621    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Google Scholar Articles by Abreu, J. R.F. Articles by Reedquist, K. A. PubMed PubMed Citation Articles by Abreu, J. R.F. Articles by Reedquist, K. A. Pubmed/NCBI databases Medline Plus Health Information Joint Disorders Rheumatoid Arthritis

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^* and Kris A. Reedquist^*

^*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.

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