SLC27A2, a critical metabolic regulator of T cellular inflammation in juvenile idiopathic arthritis and beyond?

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Juvenile idiopathic arthritis (JIA) is a disease of unknown origin in which cells of the innate immune system as well as of the adaptive immune system including T cells play central roles. T cellular function and fate decision critically depends on energetic properties including glycolysis or oxidative phosphorylation. Fatty acids are one of the most important sources of energy for oxidative phosphorylation. Within our preliminary data we show that1. the uptake of free fatty acids is enhanced in synovial fluid (SF) CD4+ T cells of patients with JIA, 2. the expression of SLC27A2/FATP2 is increased in SF CD4+ T cells, 3. the expression of SLC27A2 and uptake of free fatty acids is enhanced in blood derived CD4+ memory T cells after stimulation with anti-CD3/CD28, 4. the uptake of free fatty acids in anti-CD3/CD28-stimulated CD4+ T cells can be blocked with lipofermata, a specific inhibitor of SLC27A2 and5. the blockade with lipofermata inhibits T cell proliferation, IFNy production and mitochondrial respiration.Our data provide strong evidence that SLC27A2 might act as a critical fatty acid transport protein which is necessary for the proliferation and inflammatory propensities of memory T cells in JIA. This suggests that SLC27A2 is a novel therapeutic target in JIA and other autoimmune diseases. Several questions arise from the above-mentioned data:A)What are the functional consequences of fatty acid uptake in SF T cells and does this alter inflammatory cues within the cells? We will identify the fatty acid composition in SF using mass-spectrometry and perform metabolite analyzes after fatty acid uptake in JIA T cells. We will perform RNAseq of memory T cells and JIA SF T cells after incubation with lipofermata and stimulation with anti-CD3/CD28. B)Is T cell differentiation and function affected by SLC27A2 expression? Human and murine naïve CD4 T cells will be differentiated into Th1/Th2/Th17/Treg cells in the presence/absence of lipofermata as well as siRNA for SLC27A2. We will generate CD4CRESLC27A2fl/fl mice and analyze them with regard to T cell compartments, metabolism, transcriptional and function.C)What is the reason for SLC27A2 upregulation in JIA memory T cells? ATACseq will be performed in SF T cells as well as in stimulated and unstimulated memory T cells to decipher chromatin accessibility and to identify transcription factor binding sites within the promoter/enhancer regions.D)Can blockade of SLC27A2 prevent experimental arthritis? We will perform a Collagen- induced arthritis model in CD4CRESLC27A2fl/fl mice and controls as well as a T cell-mediated transfer arthritis model using lipofermata as therapeutic intervention. Our project will clarify the role of SLC27A2 for the energetic demands of CD4+ memory T cells in JIA. If our preliminary data hold true, we would have identified a novel concept of fatty acid uptake and metabolism in CD4+ memory T cells with the chance to specifically target it in inflammatory diseases.