Reduction of pro-inflammatory effector functions through remodeling of fatty acid metabolism in CD8+ T-cells from Rheumatoid Arthritis patients

Abstract

AbstractObjectivesRA 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.MethodsThe 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.ResultsThe 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.ConclusionsRA 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.