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.
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.
Abreu
Joana R F
JR
Academic Medical Center, University of Amsterdam, The Netherlands.
Grabiec
Aleksander M
AM
Krausz
Sarah
S
Spijker
René
R
Burakowski
Tomasz
T
Maslinski
Wlodzimierz
W
Eldering
Eric
E
Tak
Paul P
PP
Reedquist
Kris A
KA
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
D011948:Receptors, Antigen, T-Cell