Objective. Rheumatoid arthritis (RA) CD8+ T cells maintain their effector proinflammatory phenotype by changing their metabolism toward aerobic glycolysis. However, their massive energy and biosynthesis needs may require additional substrates other than glucose. Since systemic alterations in lipid metabolism have been reported in RA patients, we explored the role of fatty acid (FA) metabolism in CD8+ T cells to identify potential targets to curb their proinflammatory potential.Methods. The expression of FA metabolism-related genes was analyzed for total CD8+ T cells and CD8+ T cell subsets in the data of RA patients and healthy controls retrieved from the GEO database. Functional assays were performed using peripheral blood CD8+ T cells isolated from RA (n = 31), psoriatic arthritis (n = 26), and spondyloarthritis (n = 21) patients receiving different therapies (disease-modifying antirheumatic drugs, biologics, and JAK inhibitors) and from healthy controls (n = 14). We quantified the expression of FA transporters, lipid uptake, intracellular FA content, cytokine production, activation, proliferation, and capacity to inhibit tumor cell growth, either with or without FA metabolism inhibitors.Results. The CD8+ T cell gene expression profile of FA metabolism-related genes was significantly different between untreated RA patients and healthy controls. RA patients who had a good clinical response after 6 months of methotrexate therapy had significantly increased expression of FA metabolism-related genes. Cell surface expression of the FA transporters FA binding protein 4 (FABP4) and G protein-coupled receptor 84 (GPR84) and FA uptake were higher in effector and memory CD8+ T cells from RA patients compared to those from healthy controls. In vitro blockade of FA metabolism significantly impaired CD8+ T cell effector functions.Conclusion. RA CD8+ T cells present an altered FA metabolism, which could provide potential therapeutic targets to control their proinflammatory profile, particularly therapies directed against the transport and oxidation of free FA.

Objectives: RA CD8+ T-cells (CD8) maintain their effector pro-inflammatory phenotype by changing their metabolism towards aerobic glycolysis. However, their massive energetic and biosynthetic needs may require additional substrates to furnish this high demand. Since systemic alterations in lipid metabolism have been reported in RA patients, we explored the role of fatty acid (FA) metabolism in CD8 to identify potential targets to curb their pro-inflammatory potential. Methods: The expression of FA metabolism-related genes was analyzed for total and CD8-subsets from RA patients and healthy controls (CNT). Peripheral-blood CD8 were isolated from RA, PsA, SpA patients under different therapies (DMARD, biologicals, JAK-inhibitors) and CNT and were TCR-stimulated with or without FA metabolism inhibitors. We quantified the expression of the main FA transporters, lipid uptake, intracellular content of (un-)saturated FA, cytokine production, activation, proliferation, and capacity to inhibit tumor cell growth. Results: The CD8 gene expression profile of FA metabolism-related genes was significantly different between untreated RA patients and CNT. RA patients with a good clinical response after 6 months MTX therapy significantly increased the expression of FA metabolism-related genes. Cell-surface expression of FA transporters FABP4 and GPR84 and FA-uptake was higher in effector and memory CD8 of RA patients than for CNT. In vitro blockade of FA metabolism significantly impaired CD8 effector functions. Conclusions: RA CD8 present an altered FA-metabolism which can be potential therapeutic targets to control their pro-inflammatory profile, especially by targeting the transport and oxidation of free FAs which are abundant in the serum and synovial fluid of patients.