LncRNA PVT1 links Myc to glycolytic metabolism upon CD4+ T cell activation and Sjögren's syndrome-like autoimmune response

The hyperproliferation and hyperactivation of CD4+ T cells in salivary gland tissue is a hallmark of Sjögren's syndrome (SS). However, the role of long noncoding RNAs (lncRNAs) in the pathological process of SS and CD4+ T cell activation has not been fully elucidated. Here, we reported that lncRNA PVT1 was involved in the glycolytic metabolism reprogramming and proliferation upon CD4+ T cell activation. Expression of PVT1 was positively related with CD4+ T cell activation both in SS patients and Ex vivo antigen simulation. Depletion of PVT1 decreased the proliferation of murine CD4+ T cells and Jurkat T cells upon activation. We also showed that expression of the transcription factor Myc is regulated by PVT1 under antigen simulation. Depletion of PVT1 significantly decreased the expression of glycolytic genes, as well as several pivotal glycolytic proteins that were directly transcribed by Myc. Measurement of glucose content and lactate secretion indicated a defected lactate secretion and glucose uptake in PVT1-depleted T cells. Additionally, the real-time extracellular acidification rate (ECAR) and oxygen consumption rate (OCR) measurement also affirmed that PVT1 maintains glycolytic levels, glycolytic capacity under stress and ECAR/OCR ratios during T cell activation. Polarizing assays indicate that PVT1 depletion defected the function of Th1 effector cells as well as down-regulated Myc expression and glycolytic levels. Furthermore, we observed increased glycolytic levels in CD4+ T cells from SS-like NOD/Ltj mice. Treatment with 2-deoxy-d-glucose (2-DG), an inhibitor of glycolysis, significantly decreased the extent of lymphocyte infiltration and CD4+ T cell numbers and attenuated the defect of salivary flow in the lesioned submandibular glands of NOD/Ltj mice. Thus, our study demonstrated that lncRNA PVT1, which was upregulated in the CD4+T cells of SS patients, could maintain the expression of Myc, thus controlling the proliferation and effector functions of CD4+ T cells through regulating the reprogramming of glycolysis. Inhibition of glycolysis could attenuate the proliferation of CD4+ T cells and the SS-like autoimmune response. Our study provides a novel mechanistic function of lncRNA PVT1 in the pathogenesis of SS.