title: 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.
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-alpha, and IFN-gamma) 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.
authors.affiliation: Academic Medical Center, University of Amsterdam, The Netherlands.
authors.forename: Joana R F
authors.initials: JR
authors.lastname: Abreu
authors.forename: Aleksander M
authors.initials: AM
authors.lastname: Grabiec
authors.forename: Sarah
authors.initials: S
authors.lastname: Krausz
authors.forename: René
authors.initials: R
authors.lastname: Spijker
authors.forename: Tomasz
authors.initials: T
authors.lastname: Burakowski
authors.forename: Wlodzimierz
authors.initials: W
authors.lastname: Maslinski
authors.forename: Eric
authors.initials: E
authors.lastname: Eldering
authors.forename: Paul P
authors.initials: PP
authors.lastname: Tak
authors.forename: Kris A
authors.initials: KA
authors.lastname: Reedquist
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis / Q000276:immunology*; D001172:Arthritis, Rheumatoid / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D049109:Cell Proliferation; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D011948:Receptors, Antigen, T-Cell / Q000172:deficiency / Q000502:physiology*; D015398:Signal Transduction / Q000276:immunology*; D013582:Synovial Fluid / Q000276:immunology / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology
chemical_list: D011948:Receptors, Antigen, T-Cell