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-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.

Mesenchymal stem cells are conditionally therapeutic in preclinical models of rheumatoid arthritis

“…The apparently ‘unorthodox’ finding of the hyporesponsive AIA splenocytes compared with normal splenocytes (figure 5A), is in agreement with the literature demonstrating the paradoxical hyporesponsiveness of ex-vivo-stimulated RA T cells, compared with normal T cells 23–25…”

N-(2-hydroxy phenyl) acetamide inhibits inflammation-related cytokines and ROS in adjuvant-induced arthritic (AIA) rats

“…A number of studies have suggested that macrophages, T lymphocytes and proliferating synovial cells are very likely to play a major role in the pathogenesis of this disease [49][50][51][52]. The pro-inflammatory cytokines such as IL-1β, IL-6, and TNF-α, produced by the activated T cells and macrophages [53] appear to be involved in the initiation and perpetuation of rheumatoid arthritis.…”

The anti-arthritic and anti-oxidative effect of NBD (6-nitro-1,3-benzodioxane) in adjuvant-induced arthritis (AIA) in rats

“…Various studies have suggested the increased production of pro-inflammatory cytokines by the activated T cells and macrophages [14][15][16][17][18][19][20][21]. These pro-inflammatory cytokines are considered to play a prominent role in the pathogenesis of rheumatoid arthritis, and the regulation of these cytokine levels in arthritic subjects is one of the approaches to the treatment of arthritis [10].…”

“…The common pathway for the RA is likely initiated by various humoral signaling agents including activation of pro-inflammatory cytokines, such as interleukin-1b (IL-1b) and tumor necrosis factor-a (TNF-a) [6][7][8][9][10][11], and production of reactive oxygen species (ROS) and reactive nitrogen species (RNS). Studies have suggested that macrophages, T lymphocytes, and proliferating synovial cells very likely play a major role in the pathogenesis of this disease by producing IL-1b, IL-6, and TNF-a [12][13][14][15][16][17][18][19][20]. Likewise, the ROS are products of normal cellular metabolism but their excessive formation is a primary cause, or a downstream consequence, of tissue injury that leads to many pathological conditions such as cancer, cardiovascular disease, atherosclerosis, and RA [21][22][23].…”