tRNA derived fragment -3009 participates in modulation of IFN-[alpha]-induced CD4+ T cell oxidative phosphorylation in lupus patients

Background Accumulating evidence suggests tRNA-derived fragments (tRFs) play important roles in cellular homeostasis. Here we aimed to explore aberrant expression of tRFs in CD4.sup.+ T cells from patients with systemic lupus erythematosus (SLE) and their potential function in the SLE pathogenesis. Methods First, small RNA sequencing was performed on CD4.sup.+ T cells from four SLE patients and three healthy controls (HCs). Candidate tRFs were then validated in CD4.sup.+ T cells from 97 SLE patients and their relevant disease controls using qRT-PCR. Then sequencing was used to investigate the profiles of HC-derived CD4.sup.+ T cells transfected with tRF-3009. Lastly, tRF-3009 siRNA or tRF-3009 mimics were transfected into CD4.sup.+ T cells with/without IFN-[alpha]. Changes in oxygen consumption rate (OCR), ATP, and ROS production were analyzed. Results We identified 482 differentially expressed tRFs from SLE CD4.sup.+ T cells and chose tRF-3009 for further analysis due to its upregulation and the positive correlations between its expression and SLEDAI, active lupus nephritis and serum IFN-[alpha] levels. In vitro, tRF-3009 over-expressing CD4.sup.+ T cell profiling and putative analysis linked this product to the type I IFN and oxidative phosphorylation (OXPHOS) pathways. Interestingly, IFN-[alpha] is capable of inducing ROS and ATP production in CD4.sup.+ T cells, while knockdown of tRF-3009 reversed this process. Overexpression of tRF-3009 in CD4.sup.+ T cells alone was sufficient to upregulate OCR, ROS, and ATP production. Conclusions Our study is the first to link aberrant tRF expression and SLE. tRF-3009 may participate in metabolic modulation of IFN-[alpha]-induced CD4.sup.+ T cell OXPHOS in lupus. Keywords: tRNA derived fragments (tRFs), Systemic lupus erythematosus (SLE), CD4.sup.+ T cells, Oxidative phosphorylation (OXPHOS), Type I interferon (IFN)