mTOR activation in CD8+ cells contributes to disease activity of rheumatoid arthritis and increases therapeutic response to TNF inhibitors

Abstract

Objective This study aimed to understand the role of mTOR in CD8+ cells in the pathogenicity of rheumatoid arthritis (RA) and the changes after treatment with biologic drugs. Methods Peripheral blood mononuclear cells (PBMCs) were isolated from 17 healthy controls and 86 patients with RA. Phosphorylation of mTOR (p-mTOR) and its clinical relevance were evaluated. The role of mTOR in CD8+ cells was also examined in vitro. Results Patients with RA who had a moderate or high disease activity, were biologic-naïve, and were refractory to MTX were enrolled in this study. The p-mTOR levels in CD8+ cells were higher in patients with RA than in healthy controls, and they positively correlated with the disease activity in such patients. However, after one year of treatment with TNF inhibitors, the p-mTOR levels in CD8+ cells were suppressed and showed a positive correlation with the treatment response, which was not observed in the abatacept-treatment group. In vitro stimulation of CD8+ cells with anti-CD3 and anti-CD28 antibodies induced mTOR phosphorylation and increased the production of granzyme B, GNLY, TNF-α, and IFN-γ but decreased the production of granzyme K. However, on treatment with TNF inhibitors, p-mTOR levels in CD8+ cells and granzyme B production decreased, while granzyme K production increased. The production of GNLY and IFN-γ was not affected by the TNF inhibitors. Conclusion These results suggested that mTOR activation in CD8+ cells may be a novel evaluation marker for RA disease activity and a predictive marker of therapeutic response to TNF inhibitors.

Altered Transcriptional Regulation of Glycolysis in Circulating CD8+ T Cells of Rheumatoid Arthritis Patients

“…CD8 + T cells in RA patients are known to have activated mTOR [ 42 ]. The DEGs that are mapped to the mTOR signalling pathway are shown in Figure 13 .…”

“…The effect of mTOR signalling on glycolysis is mediated by HIF1A and MYC upregulation [ 27 ]. The activation of mTOR was demonstrated in the CD8 + T cells of RA patients [ 42 ].…”

“…The effect of mTOR signalling on glycolysis is mediated by HIF1A and MYC upregulation [27]. The activation of mTOR was demonstrated in the CD8 + T cells of RA patients [42]. In general, most of the considered genes that show significant differential expressions in RA CD8 + Tem cells show similar but non-significant differential expressions in the same direction in the RA CD8 + Temra cells (Figure 11).…”

Pathogenesis of rheumatoid arthritis: one year in review 2023

“…Interestingly, the levels of the phosphorylated (p) form of mTOR resulted higher in RA CD8 + cells compared to healthy CD8 + cells. Furthermore, p-mTOR levels positively correlate with disease activity and, following in-vitro stimulation, these cells were able to produce granzyme B, granulysin, TNF-α and IFN in parallel to the decrease production of granzyme K. Interestingly, following treatment with TNF-α inhibitors, the levels of p-mTOR levels decreased, suggesting that mTOR activation could be a potential therapeutic target in RA (51).…”

Rapamycin Dampens Inflammatory Properties of Bone Marrow ILC2s in IL-33-Induced Eosinophilic Airway Inflammation

“…The mechanistic target of rapamycin (mTOR) signaling pathway regulates many cellular processes including cell metabolism, migration, differentiation and cytokine responses (22,23). The mTOR signaling pathway is implicated in several inflammatory diseases (23)(24)(25)(26)(27) and rapamycin, an inhibitor of mTOR Complex 1 (mTORC1), can suppress eosinophil differentiation in both allergic and non-allergic airway inflammation (28)(29)(30). Zhang et al reported that eosinophil infiltration in mouse lung was impaired after treatment with rapamycin and other mTOR inhibitors in an ovalbumininduced asthma model (31).…”